inorganics
Perspective
Integrative Metallomics Studies of Toxic Metal(loid) Substances
at the Blood Plasma–Red Blood Cell–Organ/Tumor Nexus
Maryam Doroudian and Jürgen Gailer *
Department of Chemistry, 2500 University Drive NW, University of Calgary, Calgary, AB T2N 1N4, Canada
* Correspondence: jgailer@ucalgary.ca
Abstract: Globally, an estimated 9 million deaths per year are caused by human exposure to environmental pollutants, including toxic metal(loid) species. Since pollution is underestimated in
calculations of the global burden of disease, the actual number of pollution-related deaths per year is
likely to be substantially greater. Conversely, anticancer metallodrugs are deliberately administered
to cancer patients, but their often dose-limiting severe adverse side-effects necessitate the urgent
development of more effective metallodrugs that offer fewer off-target effects. What these seemingly
unrelated events have in common is our limited understanding of what happens when each of these
toxic metal(loid) substances enter the human bloodstream. However, the bioinorganic chemistry
that unfolds at the plasma/red blood cell interface is directly implicated in mediating organ/tumor
damage and, therefore, is of immediate toxicological and pharmacological relevance. This perspective
will provide a brief synopsis of the bioinorganic chemistry of AsIII , Cd2+ , Hg2+ , CH3 Hg+ and the
anticancer metallodrug cisplatin in the bloodstream. Probing these processes at near-physiological
conditions and integrating the results with biochemical events within organs and/or tumors has the
potential to causally link chronic human exposure to toxic metal(loid) species with disease etiology
and to translate more novel anticancer metal complexes to clinical studies, which will significantly
improve human health in the 21st century.
Citation: Doroudian, M.; Gailer, J.
Integrative Metallomics Studies of
Keywords: toxic metal(loid)s; chronic exposure; mechanism of toxicity; metallodrugs; stability in
plasma; side effects; bloodstream; bioinorganic chemistry
Toxic Metal(loid) Substances at the
Blood Plasma–Red Blood
Cell–Organ/Tumor Nexus. Inorganics
2022, 10, 200. https://doi.org/
10.3390/inorganics10110200
Academic Editor: Navid Rabiee
Received: 9 September 2022
Accepted: 4 November 2022
Published: 7 November 2022
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Attribution (CC BY) license (https://
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4.0/).
1. Introduction
Ever since the inception of life some 3.8 billion years ago—possibly in the vicinity of
deep-sea hydrothermal vents [1]—it has been continually exposed to background concentrations of inherently toxic elements released from the earth’s crust into the biosphere by
natural processes, including volcanism and chemical weathering. Therefore, all organisms
evolved in the presence of potentially toxic metal(loid) species and had to adapt to background concentrations over millions of years [2]. A momentous event in the 1760-1780s,
however, changed the organism–earth relationship forever: the industrial revolution. This
represents the onset of the production of consumer products at an ever-increasing scale,
which required unprecedented amounts of energy (i.e., fossil fuels) and building blocks
(i.e., chemical elements). The associated advent of the mining/metallurgy industry resulted
in the increased emission of toxic metal(loid) species into the environment in many parts
of the world [3,4], which has dramatically affected ecosystems [5] and, in turn, inevitably
exposed certain human populations [6].
A conceptually related event which involved the interaction of an entirely different
type of toxic metalloid compound with humans took place in 1911: the birth of chemotherapy by Paul Ehrlich. While his synthesis of the arsenic-containing drug Salvarsan contributed to humankind’s exploration of the available ‘chemical space’ [7], its administration
to patients who suffered from syphilis—a bacterial infection caused by Treponema pallidum—ushered in a fundamentally new therapeutic approach to treat human diseases by
exploiting the concept of ‘selective toxicity’ [8,9].
Inorganics 2022, 10, 200. https://doi.org/10.3390/inorganics10110200
https://www.mdpi.com/journal/inorganics
Inorganics 2022, 10, 200
contributed to humankind’s exploration of the available ‘chemical space’ [7], its administration to patients who suffered from syphilis—a bacterial infection caused by Treponema
pallidum—ushered in a fundamentally new therapeutic approach to treat human diseases
2 of 19
by exploiting the concept of ‘selective toxicity’ [8,9].
What conceptually relates the exposure of humans to toxic metal(loid) species with
the administration of an arsenic-containing drug to patients is the fact that both of these
What conceptually
the exposure
of humans
to toxic metal(loid)
with theby Wiltoxic substances
infiltraterelates
the systemic
blood
circulation,
which wasspecies
discovered
administration of an arsenic-containing drug to patients is the fact that both of these toxic
liam Harvey [10]. His recognition that the bloodstream effectively represents a conveyor
substances infiltrate the systemic blood circulation, which was discovered by William Harbelt vey
which
human
with water,
life-sustaining
(es[10].supplies
His recognition
thatorgans
the bloodstream
effectively
represents aoxygen
conveyorand
beltnutrients
which
sential
elements,
andoxygen
lipids)and
to nutrients
maintain
humanelements,
health makes
supplies
humanvitamins,
organs withcarbohydrates
water, life-sustaining
(essential
carbohydrates
to maintain
human adverse
health makes
this biological
fluid toxic
this vitamins,
biological
fluid oneand
of lipids)
the first
sites where
interactions
between
one of thespecies/cytotoxic
first sites where adverse
interactions and
between
toxic metal(loid)
species/cytotoxic
metal(loid)
metallodrugs
constituents
of the
bloodstream unfold
metallodrugs
and
constituents
of
the
bloodstream
unfold
(Figure
1)
[11,12].
The interactions
toxi(Figure 1) [11,12]. The toxicological and pharmacological relevance of these
cological and pharmacological relevance of these interactions with constituents of the
with constituents of the bloodstream is attributed to the simple fact that they collectively
bloodstream is attributed to the simple fact that they collectively constitute a ‘filter’ which
constitute
a ‘filter’determines
which fundamentally
determines which
toxic-metal-containing
fundamentally
which toxic-metal-containing
species
or metabolites thereof species
or metabolites
will
impinge
organs to cause
either
a detrimental
effect, in the
will impingethereof
on organs
to cause
eitheron
a detrimental
effect, in
the case
of toxic metal(loid)
a desirable
pharmacological
effect in the
case of anticancer effect
metallodrugs
casespecies,
of toxicand/or
metal(loid)
species,
and/or a desirable
pharmacological
in the case of
on a malignant
tumor. on a malignant tumor.
anticancer
metallodrugs
Figure
1. The
rolerole
heldheld
by the
bioinorganic
chemistry
speciesand
and metalFigure
1. central
The central
by the
bioinorganic
chemistryof
oftoxic
toxic metal(loid)
metal(loid) species
lodrugs
in the bloodstream
in termsinofterms
linking
environmental
exposure
to adverse
health
effects/ormetallodrugs
in the bloodstream
of linking
environmental
exposure
to adverse
health
gan-based
diseases
and
in
developing
better
drugs
to
treat
human
diseases,
such
as
cancer
effects/organ-based diseases and in developing better drugs to treat human diseases, such as cancer (Figure
modified
from
[13]).from [13]).
(Figure
modified
Considerable
progress has
has been
conceptually
relate
toxic toxic
metal(loid)
species species
Considerable
progress
beenmade
madetoto
conceptually
relate
metal(loid)
and metallodrugs—which will from now on be referred to as toxic metal(loid) substances—
and inmetallodrugs—which
will from now on be referred to as toxic metal(loid) subbiological systems to adverse or intended human health effects. It is, therefore, timely
stances—in
biological
systems
to adverse as
orto
intended
health
effects. It
therefore,
to provide the reader with a perspective
why the human
bioinorganic
chemistry
of is,
toxic
timely
to provide
the reader
with in
a perspective
as to
theabioinorganic
chemistry of
metal(loid)
substances,
specifically
the bloodstream,
haswhy
become
worthwhile research
avenue.
Since
the
available
experimental
techniques
to
measure
metal-containing
metabotoxic metal(loid) substances, specifically in the bloodstream, has become a worthwhile
lites in
biological
fluids
not ourexperimental
primary focus,techniques
the interested
reader is referred
to
research
avenue.
Since
theare
available
to measure
metal-containing
relevant reviews [14–18]. Nevertheless, a few techniques that are particularly approprimetabolites
in biological fluids are not our primary focus, the interested reader is referred
ate to solve relevant problems will be outlined. Then, bioinorganic mechanisms of toxic
to relevant
reviews
[14–18].
Nevertheless,
techniques
thatconceptual
are particularly
approprimetal(loid)
species
in the bloodstream
will a
befew
presented,
and their
link to adate to
solve
relevant
problems
will
be
outlined.
Then,
bioinorganic
mechanisms
verse health effects will be discussed. This section will be followed by an analogous brief of toxic
metal(loid) species in the bloodstream will be presented, and their conceptual link to adverse health effects will be discussed. This section will be followed by an analogous brief
Inorganics 2022, 10, 200
3 of 19
summary of the biochemical fate of anticancer metallodrugs in the bloodstream. Finally,
we underscore the importance of integrating processes involving toxic metal(loid) substances in the bloodstream with those that happen in organs in terms of understanding
their impact at the whole-organism level, either negatively (toxicology) or advantageously
(pharmacology).
2. Critical Importance of Studying Toxic Metal(loid) Substances in the Bloodstream
(Footnote: From Now on We Use the Term ‘Substances’ When We Refer to Both Toxic
Metal(loid) Species and Metallodrugs)
The man-made emission of toxic metal(loid) species into the environment has gradually increased since the onset of the Industrial Revolution, and perturbs the global biogeochemical element cycles of at least 11 elements today, with arsenic (As), cadmium (Cd) and
mercury (Hg) species critically affecting air, water and food [19]. In fact, the input of Hg to
ecosystems is estimated to have increased two- to five-fold during the industrial era [20].
These profound geochemical changes in the biosphere have prompted some scientists to
refer to our age as the ‘Anthropocene’ [21]. Certain human populations, including children,
are therefore unwittingly exposed to higher daily doses of persistent inorganic environmental pollutants through the ingestion of contaminated food [22–25], the inhalation of
contaminated air [26–29] and/or dermal exposure to consumer products [30–32] than ever
before. Unsurprisingly, pollution has become the world’s largest environmental cause of
disease and premature death, with an estimated ~9 million deaths per year [33] and is
associated with staggering global healthcare costs [34]. Owing to the inherent persistence
of As, Cd and Hg species and their binding to hematite and humic acids in soils [35], their
concentrations in ecosystems will either remain constant—potentially for millennia [36,37]—
or even gradually increase over time [38,39]. Due to the continued consumption of large
quantities of Hg [40], the global-warming-induced re-mobilization of certain metal(loid)
species [41] and the ongoing contamination of the food chain with these inorganic pollutants [22,25,42,43], the concomitant exposure of human populations represents a global
health problem [44–46]. Owing to the severe health effects associated with human exposure
to comparatively small daily doses of toxic metal(loid) species (up to 260 µg/day), the
toxicology of metals has received considerable research attention [6,47], which has in turn
resulted in the implementation of guidelines for maximum permissible concentrations
in drinking water [48], food [22] and air [49] in many countries. As a consequence of
additional human exposure to these inorganic pollutants through consumer products [30],
personal care products [32], nanomaterials [50] and the global-warming-induced increase
in using wastewater for food irrigation [44], an emerging challenge is the establishment of
a new paradigm to assess how a lifetime of exposure affects the risk of developing chronic
diseases [51]. In this context, the elucidation of the biomolecular mechanisms of toxicity
associated with chronic human exposure to toxic metal(loid) species [52,53] and causally
linking these mechanisms with the etiology of human illnesses that do not have a genetic
origin [54] remain perhaps the two most pertinent knowledge gaps.
The development of chemotherapy to treat human diseases other than bacterial infections was—somewhat counterintuitively—accelerated during World Wars I and II, when
certain warfare agents were used for the first time. In particular, the observation that
soldiers’ exposure to nitrogen mustards specifically targeted bone marrow cells prompted
scientists to investigate if this effect may be harnessed to selectively target malignant cells.
By the mid-1960s, the anticancer metallodrug cisplatin was serendipitously discovered [55]
and FDA-approved in 1978. Despite cisplatin being a ‘shotgun’ cytotoxin (it does not
differentiate between cancer and healthy cells), which is intrinsically associated with severe
and dose-limiting side-effects [56], close to 50% of all cancer patients worldwide are today
treated with cisplatin, carboplatin and/or oxaliplatin, either by itself or in combination
with other anticancer drugs [12]. The success story of cisplatin triggered intense research
efforts to develop metallodrugs for use as photochemotherapeutic drugs, antiviral drugs,
antiarthritic drugs, antidiabetic drugs, drugs for the treatment of cardiovascular and gastrointestinal disorders as well as psychotropics [57], but overall metallodrugs remain a tiny
Inorganics 2022, 10, 200
4 of 19
minority of all medicinal drugs that are currently on the market [58,59]. The considerable
burden of cancer on the world economy [60], however, necessitates the urgent development
of more effective anticancer drugs that offer higher selectivity and, thus, fewer side-effects
to improve the quality of life of patients during and after cancer treatment. Even though
promising novel anticancer metal complexes are being developed [9,61], advancing more
of these to preclinical/clinical studies remains a major problem [12]. This problem is
attributed to the fact that insufficient attention is being directed to assess the effect of pharmacologically relevant doses of novel anticancer metal complexes on (a) the integrity of red
blood cells (RBCs) [62], (b) their stability in blood plasma [12,63] and (c) their selectivity
toward cancer cells versus healthy cells [64].
3. General Considerations Pertaining to Interactions of Toxic Metal(loid) Substances
in Humans
With regard to the infiltration of the bloodstream by a toxic metal(loid) species, a
reasonable question to ask is how an exceedingly small daily dose (e.g., 200 µg of inorganic As/day will eventually result in cancer [65]) can reach target organs. Interactions
of toxic metal(loid) species with some bloodstream constituents are ‘good’, as their initial
binding/sequestration (e.g., binding to human serum albumin or uptake into RBCs) will
delay/preclude it from reaching a target organ. Conversely, a metallodrug that is intravenously administered is intended to reach the malignant tumor intact in order to cause
maximal damage. Hence, any interaction(s) of an anticancer metallodrug with bloodstream
constituents (e.g., a partial decomposition followed by plasma protein binding) is/are ‘bad’,
as less will reach the tumor tissue.
It is important to point out that the daily human exposure to toxic metal(loid) species
by inhalation and ingestion is comparatively lower (µg/day) than that of anticancer metallodrugs, which are intravenously administered (mg/day). It is, therefore, not entirely
surprising that an extensive lag-time can exist between the onset of chronic human exposure
to toxic metal(loid) species and the start of overt adverse health effects [52], while overt
signs of toxicity manifest themselves typically within hours or days after the intravenous
administration of patients with anticancer metallodrugs [56].
The challenge that pertains to both types of these toxic metal(loid) substances is
the need to establish the entire sequence of bioinorganic interactions that occur at the
plasma/RBC interface and to integrate them with processes that unfold in organs/tumors
(Figure 2). For toxic metal(loid) species, this means revealing the biomolecular mechanisms
causing organ damage; for metallodrugs, it also implies screening novel molecular structures which preferentially target the tumor cells, while leaving healthy organs unscathed.
Ironically, the effect of these toxic metal(loid) substances on human health are conceptually
intertwined in an interesting manner, since specific toxic metal(loid) species are established
carcinogens (e.g., inorganic As and Cd [66,67]), while cancer patients are being treated with
highly cytotoxic metallodrugs (e.g., cisplatin) to achieve tumor shrinkage/remission that
are often associated with severe side-effects.
Inorganics
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Figure 2. Conceptual relationship of bioinorganic processes in the bloodstream following (a) the
Figure 2. Conceptual relationship of bioinorganic processes in the bloodstream following (a) the
chronic exposure of humans to a toxic metal(loid) species (toxicological effect) and (b) the intravechronic
exposure of humans
to apatients
toxic metal(loid)
speciesmetallodrug
(toxicological(pharmacological
effect) and (b) theeffect).
intravenous
nous
administration
by cancer
of an anticancer
administration by cancer patients of an anticancer metallodrug (pharmacological effect).
4.
4.Bioinorganic
BioinorganicChemistry
Chemistryof
ofToxic
Toxic Metal(loid)
Metal(loid) Substances
Substances in
in the
the Bloodstream
Bloodstream In
In
Vitro/In
Vitro/In Vivo
Vivo
One
One of
of the
the main
maindifficulties
difficultiesof
of studying
studyingchemical
chemicalreactions
reactionsthat
thatunfold
unfoldin
inthe
thebloodbloodstream
complexity,
which
is directly
related
to itstoorchestration
of theofconstreamisisits
itsbiological
biological
complexity,
which
is directly
related
its orchestration
the
tinual
exchange
of nutrients
absorbed
from from
the GIthe
tract
organs
and theand
eventual
excrecontinual
exchange
of nutrients
absorbed
GItotract
to organs
the eventual
tion
of waste
products
via thevia
kidneys.
The bloodstream
should not,
however,
be viewed
excretion
of waste
products
the kidneys.
The bloodstream
should
not, however,
be
as
a
seamless
pipe,
since
it
contains
up
to
10,000
plasma
proteins
[68],
>400
SMW
metabviewed as a seamless pipe, since it contains up to 10,000 plasma proteins [68], >400 SMW
olites
[69] and[69]
~1600
cytosolic
proteinsproteins
[70] which
can
engage
a variety
potential
metabolites
andRBC
~1600
RBC cytosolic
[70]
which
caninengage
in of
a variety
of
chemical
toxicwith
metal(loid)
substances.
The enormous
number ofnumber
potential
potential reactions
chemical with
reactions
toxic metal(loid)
substances.
The enormous
of
binding
on plasma
metabolites,
for example,
resultcan
in their
potentialsites
binding
sites onproteins/SMW
plasma proteins/SMW
metabolites,
for can
example,
resultrein
versible
vs. irreversible
binding binding
[71], while
the
partial
complete
sequestration
of toxic
their reversible
vs. irreversible
[71],
while
theorpartial
or complete
sequestration
of toxic metal(loid)
substances
within
RBCspreclude
would preclude
theirtoinflux
target organs.
metal(loid)
substances
within RBCs
would
their influx
targettoorgans.
Given
Given
the
reducing
conditions
within
RBCs,
redox
reactions
of
toxic
metal(loid)
substances
the reducing conditions within RBCs, redox reactions of toxic metal(loid) substances
within RBCs
RBCs must
must also
also be
be considered.
considered. The
The intrinsic
intrinsic biological
biologicalcomplexity
complexityof
of plasma
plasma and
and
within
RBC cytosol
cytosol can
can be
be overcome
overcome by
by using
using metallomics
metallomics tools,
tools, which
which refers
refers to
to hyphenated
hyphenated
RBC
techniquesthat
thatare
arecomprised
comprisedof
ofaaseparation
separationmethod
method(e.g.,
(e.g.,HPLC,
HPLC,2D-PAGE)
2D-PAGE)coupled
coupledto
to
techniques
an element-specific
element-specific detection
detection technique
technique [14–16,72].
[14–16,72]. The
The application
application of
of metallomics
metallomics tools
tools
an
inherently reduces the
significantly,
as the
number
of endogeinherently
theanalytical
analyticalseparation
separationproblem
problem
significantly,
as the
number
of ennous
metal
species
within
any
given
biological
fluid
(e.g.,
all
endogenous
metalloproteins)
dogenous metal species within any given biological fluid (e.g., all endogenous metallorepresents
a sub-proteome
of the proteome
(i.e., all proteins
a biological
fluid).
proteins)
represents
a sub-proteome
of the proteome
(i.e., allwithin
proteins
within a biological
fluid).Detecting complexes containing a chemical bond between a toxic and an essential
element,
for example,
in blood
plasma,
would reveal
which essential
traceanelement
is
Detecting
complexes
containing
a chemical
bond between
a toxic and
essential
targeted
by
a
particular
toxic
metal(loid)
species
[73].
Since
blood
is
comprised
of
about
element, for example, in blood plasma, would reveal which essential trace element is tar50% ofbyRBCs,
it is alsotoxic
of importance
consider
theSince
binding
of is
toxic
metal(loid)
species
to
geted
a particular
metal(loid)tospecies
[73].
blood
comprised
of about
50%
the
lipid
bilayer
membrane
of
intact
RBCs
[74]
and
the
cytosolic
proteins
within
RBCs
[75].
of RBCs, it is also of importance to consider the binding of toxic metal(loid) species to the
In terms
of membrane
anticancer of
metallodrugs,
theirand
metabolism
in proteins
the bloodstream
can [75].
lead In
to
lipid
bilayer
intact RBCs [74]
the cytosolic
within RBCs
the
formation
of
hydrolysis
products,
which
can
then
bind
to
plasma
proteins,
such
as
terms of anticancer metallodrugs, their metabolism in the bloodstream can lead to the forhumanof
serum
albumin
(HSA).which
It is therefore
to analyze
bloodsuch
plasma
for all
mation
hydrolysis
products,
can thendesirable
bind to plasma
proteins,
as human
Inorganics 2022, 10, x FOR PEER REVIEW
6 of 19
Inorganics 2022, 10, 200
6 of 19
serum albumin (HSA). It is therefore desirable to analyze blood plasma for all parent
metal-containing
metabolites,
whichwhich
has been
attained
for cisplatin
and carparent metal-containing
metabolites,
has successfully
been successfully
attained
for cisplatin
and
boplatin
[76].
carboplatin [76].
In
In addition
addition to
to analyzing
analyzing plasma
plasma and
and RBC
RBC cytosol,
cytosol, one
one should
should also
also heed
heed the
the advice
advice
from
R.J.P.
Williams
that
‘living
organisms
cannot
be
understood
by
studying
extracted
from R.J.P. Williams that ‘living organisms cannot be understood by studying extracted
(dead)
(dead) molecules.
molecules. We
We have
have to
to study
study flow
flow systems’
systems’ [77].
[77]. Accordingly,
Accordingly, conducting
conducting in
in vivo
vivo
experiments
usinganimal
animalmodels
modelsis is
invaluable
it can
provide
an important
starting
experiments using
invaluable
as itascan
provide
an important
starting
point
point
for further
research.
For example,
may
be possible
to identify
a particular
complex
for further
research.
For example,
it mayitbe
possible
to identify
a particular
complex
which
which
contains
a
chemical
bond
between
a
toxic
and
an
essential
element
[78,79]
which
contains a chemical bond between a toxic and an essential element [78,79] which can
then
can
thenstudies
initiate
tothe
establish
the entire mechanism
of chronic toxicity/pharmacoinitiate
to studies
establish
entire mechanism
of chronic toxicity/pharmacological
action
logical
action
within the bloodstream–organ
Tolab
thishas
end,
our lab has
within the
bloodstream–organ
system (Figuresystem
2). To (Figure
this end,2).our
demonstrated
demonstrated
that the
of AsIII is fundamentally
to that oftrace
the essential
that the metabolism
of metabolism
AsIII is fundamentally
tied to that of tied
the essential
element
trace
element
selenium.
After the injection
intravenous
injection
of rabbits
with
As
and
SeIV, the
selenium.
After
the intravenous
of rabbits
with
AsIII and
SeIV
, III
the
analysis
of
analysis
of revealed
rabbit bile
an As:Se
of 1:1,
which
in vivo and
forrabbit bile
anrevealed
As:Se molar
ratiomolar
of 1:1,ratio
which
implied
theimplied
in vivothe
formation
mation
and
an As-Sefrom
compound
from
thelatter
liver.compound
The latter was
compound
was
excretion
of excretion
an As-Se of
compound
the liver.
The
structurally
structurally
characterized
as the seleno-bis(S-glutathionyl)
arsinium
ion [(GS)
2AsSe
][78],
characterized
as the seleno-bis(S-glutathionyl)
arsinium ion
[(GS)2 AsSe
] [78],
which
is
which
formed intracellularly
formedisintracellularly
followingfollowing
Equationeqn
1. 1.
- 3- + 8GSH (GS)2AsSe
- - + 3GSSG + 6H2O
As(OH)
3 + HSeO
As(OH)
3 + HSeO3 + 8GSH → (GS)2 AsSe + 3GSSG + 6H2 O
(1)
(1)
Notably, the results from this in vivo experiment were crucial to design subsequent
Notably, the
results
from this
vivo
experiment were crucial to design subsequent
investigations,
which
revealed
thatin(GS)
2AsSe- is formed in the bloodstream [80] (Figure
investigations, which revealed that (GS)2 AsSe- is formed in the bloodstream [80] (Figure 3).
3). More recent experiments revealed that this metabolite is present in the liver, the gall
More recent experiments revealed that this metabolite is present in the liver, the gall
IV
bladder and the GI tract [81], and experiments with rabbits revealed that this AsIIIIII-SeIV
bladder and the GI tract [81], and experiments with rabbits revealed that this As -Se
antagonism is of direct environmental relevance [82]. Similarly, the formation and strucantagonism is of direct environmental relevance [82]. Similarly, the formation and structural
tural characterization of a Hg- and Se-containing detoxification product that is rapidly
characterization of a Hg- and Se-containing detoxification product that is rapidly formed
formed in rabbit blood was first observed in vivo [79]. The formation of the detoxification
in rabbit blood was first observed in vivo [79]. The formation of the detoxification product
product (HgSe)100SelP (Figure 3) could not have been observed in blood plasma or RBCs
(HgSe)100 SelP (Figure 3) could not have been observed in blood plasma
or RBCs alone, as
alone, as its mechanism of formation involves the reduction
of SeIV to HSe- within RBCs
its mechanism of formation involves the reduction of SeIV to HSe- within RBCs followed
by
followed by its subsequent excretion into plasma where it then reacts
with Hg2+. These
2+
its subsequent excretion into plasma where it then reacts with Hg . These few examples
few examples underscore the vital role that in vivo studies play in the context of discovunderscore the vital role that in vivo studies play in the context of discovering novel
ering novel metabolites of toxicological importance.
metabolites of toxicological importance.
Figure 3.
3. Bioinorganic
Bioinorganic chemistry
chemistry of
of toxic
toxic metal(loid)
metal(loid) species
species that
that unfold
unfold in
in plasma
plasma (yellow)
(yellow) and
and red
red
Figure
blood
cells
(red)
are
critical
to
establish
their
mechanism
of
chronic
toxicity,
which
determines
the
degree
blood cells (red) are critical to establish their mechanism of chronic toxicity, which determines the
of organofdamage
over weeks/months/years.
Abbreviations:
red bloodred
cells
(RBC),
small
molecular
degree
organ damage
over weeks/months/years.
Abbreviations:
blood
cells
(RBC),
small
weight (SMW), hemoglobin (Hb), selenoprotein P (SelP), haptoglobin (Hp), glutathione (GSH).
Inorganics 2022, 10, 200
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5. Toxic Metal(loid) Species at the Plasma–RBC–Organ Nexus
From a conceptual point of view, the ‘missing link’ in the toxicology of metal(loid)
species ultimately lies in causally linking molecular data with human health effects [83].
At face value, this problem translates to an enormous transdisciplinary chemistry–biology
problem because ‘molecular data’ refers to toxicologically relevant interactions of any given
toxic metal(loid) species with biomolecules in the bloodstream [84] and in target organs [85]
which then collectively result in a specific adverse health effect at the whole organism level
(e.g., kidney damage). Understanding the associated exposure–response relationship is
critically dependent on predicting how much organ damage a toxic metal(loid) species
absorbed into the bloodstream (AsIII , Cd2+ , Hg2+ and CH3 Hg+ ) can ultimately inflict. This
goal requires one to unravel toxicologically relevant bioinorganic events in the bloodstream,
which can involve chemistry of the toxic metal(loid) species in plasma (Figure 3, yellow
arrows) [84] and/or in RBCs (Figure 3, red arrows) [75]. While these events can be studied
separately, one must integrate the results to establish the metabolism of the toxic metal(loid)
species at the plasma–RBC interface (see the bidirectional arrows between the yellow and
the red arrows in Figure 3), which ultimately determines how much of the initial dose
will be able to engage in organ damage ‘downstream’ [86]. The dynamic bioinorganic
events that unfold at the plasma–RBC–organ nexus are, in all likelihood, also responsible
for the considerable lag-phase that can exist between the onset of the chronic exposure
of an organism to toxic metal(loid) species and the time when adverse organ-based toxic
effects manifest themselves [52,87].
From a mechanistic point of view, chronic human exposure to toxic metal(loid) species
can involve three bioinorganic processes that happen in the bloodstream, which may
considerably reduce the fraction of the toxic metal(loid) species that is not ‘detoxified’
therein, and therefore, are of toxicological relevance. One important process is the sequestration of a toxic metal(loid) species within RBCs (e.g., CH3 Hg+ [88], Cd [89]) or the
formation of non-toxic complexes with essential elements, such as selenium either in blood
plasma [73] or RBCs [90] (Figure 3). Another process that needs to be considered is a
toxic-metal(loid)-species-mediated lysis of RBCs, which releases Hb to plasma where it
tightly binds to the plasma protein haptoglobin (Hp). Since the binding capacity of the
latter is limited by its plasma concentration, however, the release of too much Hb can result
in ‘free’ Hb in plasma which can then cause severe kidney damage [91]. Yet another process
by which a toxic metal(loid) species may contribute to organ damage is the gradual induction of a trace-element deficiency based on events that unfold in the bloodstream–organ
system [73,81,86].
Last but not least, one needs to consider a toxic-metal(loid)-species-induced adverse
effect on the assembly of RBCs in the bone marrow, which may adversely affect the
cytosolic concentrations of metalloproteins in the RBCs that are released into the blood
circulation [e.g., a decreased hemoglobin (Hb) concentration therein corresponds to anemia],
or may result in a decreased lifetime of RBCs in the blood circulation [92]. The exposure
of mammals to a toxic metal(loid) species can also result in the hypoproduction of the
hormone erythropoietin, which stimulates the production of RBCs and would, therefore,
result in another form of anemia [93]. Taken together, all of these individual bioinorganic
mechanisms collectively contribute to organ damage over weeks, months and possibly
years depending on the dose of the toxic metal(loid) species.
From a practical view, gaining insight into the bioinorganic chemistry of toxic metal(loid)s
in the bloodstream is hampered by its intrinsic biological complexity. The seemingly simple
task of identifying those plasma proteins that specifically bind any given toxic metal(loid)
species translates—owing to the presence of thousands of plasma proteins—into a considerable separation problem, but can be dramatically simplified by using so-called metallomics
tools [13,16]. The simultaneous detection capability of some metallomics tools allows one
to use the ~10 endogenous plasma/serum metalloproteins that contain transition metals
(Cu, Fe and Zn) (Table 1) [94,95] and the ~4 metalloproteins that are present in RBC lysate
(Table 2) as internal standards, which inherently represent molecular-weight markers and,
Inorganics 2022, 10, 200
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thus, validate an obtained analytical result. Furthermore, exogenous toxic metal(loid) species,
such as AsIII , Cd2+ , Hg2+ and CH3 Hg+ can also bind to the aforementioned metalloproteins
and/or proteins in plasma and/or RBC cytosol. In blood plasma, for example, Cd2+ has
been shown to bind to serum albumin in rats [96]. Likewise, cisplatin-derived metabolites
have been demonstrated to bind to HSA in human plasma [76], but the binding appears
to be irreversible. In this context, the irreversible binding of a metallodrug to HSA renders
the formed metallodrug–HSA complex ineffective for uptake into tumor cells [58], unless
the tumor cells can able to achieve this [97] (e.g., by macropinocytosis). Furthermore, Hg2+ ,
CH3 Hg+ and CH3 CH2 Hg+ have each been demonstrated to bind to Hb in the matrix of RBC
cytosol [75]. The formation of adducts between a toxic metal species and a metalloprotein
can have important toxicological ramifications. For example, the binding of CH3 CH2 Hg+ to
Hb is associated with its conformational change, which significantly decreases its O2 binding
capacity [98].
Table 1. Characteristics of major metalloproteins in human plasma.
Metal
Fe
Cu
Zn
Metalloprotein or Biomolecules
which Contain Bound Metal(s)
Molecular Mass
(kDa)
Number of Metal Atoms
Bound per Protein
Reference
Ferritin
450
<4500
[94]
Transferrin
79.9
1
[94]
Haptoglobin–Hemoglobin complex
86–900
2
[99]
Blood coagulation factor V
330
1
[94]
Transcuprein
270
0.5
[94]
Ceruloplasmin
132
6
[94]
Albumin
66
1
[94]
Extracellular Superoxide Dismutase
165
4
[94]
Peptides and amino acids
<5
-
[94]
α2 macroglobulin
725
5
[94]
Albumin
66
1
[94]
Extracellular Superoxide Dismutase
165
4
[94]
Table 2. Characteristics of major metalloproteins in red blood cell cytosol.
Metal
Fe
Zn
Cu
Metalloprotein
Molecular Mass
(kDa)
Number of Metal Atoms
Bound per Protein
Reference
Hemoglobin
64.5
4
[100]
Catalase
240
4
[101]
Carbonic anhydrase
30
1
[102]
Superoxide Dismutase
32
1
[103]
Superoxide Dismutase
32
1
[103]
To date, the application of LC-based metallomics tools has provided important new
insight into the bioinorganic chemistry of toxic metal(loid)s in the bloodstream (Table 3)
by observing bi- and trimetallic complexes that contain essential and toxic metals [69],
which contributed important insight into the biomolecular mechanisms that mediate organ
damage (Figure 3) [86]. In terms of probing the interaction of toxic metal(loid) species
with constituents of plasma, it is important to note that the latter contains about 400 small
molecular weight (SMW) molecules and metabolites, including amino acids, peptides,
fatty acids and nucleotides that are present at µM concentrations [104]. The variation in
concentration of these SMW molecules in the bloodstream has been demonstrated to be,
Inorganics 2022, 10, 200
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in part, genetically determined [104]. These SMW molecules and metabolites are likely to
play an important role in the distribution of toxic metal species to target organ tissues [105]
(Figure 3). Direct experimental evidence in support of this comes from a recent study
in which a metallomics tool was employed to demonstrate that homocysteine (hCys) is
critically involved in the delivery of CH3 Hg+ to L-type large neutral amino acid transporters
(LATs) [106], which mediate the uptake of CH3 Hg+ -Cys complexes into the brain [84].
hCys, an intermediate metabolite formed by the de-methylation of methionine [107], may
therefore be also involved in the translocation of other toxic metal(loid) species to target
organs. It is possible that in patients with hyperhomocysteinemia— who exhibit elevated
levels of hCys in blood plasma (e.g., >15 µM) which has been linked to the development of
cardiovascular disease, stroke, and Alzheimer’s Disease (AD) [107]—the metabolism of
toxic metal(loid)s is significantly altered and may potentially exacerbate disease progression.
Other SMW species that are also likely to be implicated in the organ uptake of toxic
metal(loid) species are Cl- and HCO3 - [108], which may therefore be indirectly implicatedin
neurodegenerative diseases [109].
6. Metallodrugs/Novel Metal(loid) Complexes at the Plasma–RBC–Organ–Tumor
Nexus
Metallodrugs [57], including cisplatin—the oldest and best-known metallodrug [110]—
are used as therapeutics for the treatment of various diseases; most prominently, cancer.
However, the severe toxic side-effects of this Pt-based anticancer metallodrug prompted
the development of other Pt-based drugs, such as oxaliplatin which kills cells by inducing
ribosome biogenesis stress rather than the cisplatin-mediated DNA-damage response [111].
An alternative strategy to develop better metallodrugs is to embrace different metals altogether, which has resulted in the synthesis of anticancer active Cu complexes as well as
ferrocene-functionalized Ru(II) arene complexes with interesting pharmacological properties [112,113]. Despite these encouraging advances, the translation of results from in vitro
studies to therapeutic success using in vivo animal models, and eventually clinical studies,
remains a major challenge. Conceptually there are two reasons why metallodrugs may
be inherently better-suited to target disease-relevant proteins than some one-dimensional
(1D, linear) or two-dimensional (2D, planar) organic molecules. Firstly, metallodrugs allow
one to build a drug molecule that provides a wider range of geometries around a metal
center in three dimensions (3D conformation) compared to 75% of linear and planar organic
FDA-approved drug molecules, which offers the possibility of more-selectively inhibiting
the active site of a target protein [114–117]. Secondly, certain metallodrugs can induce
long-lasting anticancer immune responses [118], thus offering the potential to develop
‘smart’ metallodrugs [119]. The latter term refers to drugs that more-selectively target
cancer cells, which is in accordance with the goal of achieving ‘precision medicine’ [120].
Despite these potential advantages and the fact that many novel structures are reported
annually, only a negligibly small number of novel metal(loid) complexes enter clinical studies [112,117,121]. This undesirable situation is attributed to a) the common misperception
that, similar to cisplatin [56], all metallodrugs are associated with severe toxic side-effects
and b) the challenge of translating more metal(loid) complexes through systematic in vitro
and in vivo studies to successful metallodrugs. The magnitude of the latter dilemma is
illustrated by the fact that certain metal complexes exhibit potent cytotoxicity toward
cancer cell lines in vitro, but show no antitumoral activity in vivo and may even display
nephrotoxicity [122]. These facts hint at a transdisciplinary ‘chemistry–medicine’ problem
of equal proportions to the aforementioned ‘chemistry–biology’ problem (see Section 5).
The fundamental problem that is associated with the assessment of novel metal
entities—at least in our opinion—is that their interactions with constituents of the bloodstream are often not sufficiently considered [123]. We would like to illustrate this important
bottleneck in the assessment of novel metal entities based on what is known about the fate
of cisplatin in the human bloodstream (Figure 4). While cisplatin is an ideal candidate in
this context because we know more about its biochemical fate in the bloodstream than any
Inorganics 2022, 10, x FOR PEER REVIEW
Inorganics 2022, 10, 200
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10 of 19
than any other anticancer active metallodrug, we point out that this prototypical metalother anticancer active metallodrug, we point out that this prototypical metallodrug lacks
lodrug lacks the desired tumor selectivity.
the desired tumor selectivity.
Figure 4.
4. Bioinorganic
Bioinorganicchemistry
chemistryofofcytotoxic
cytotoxicanticancer
anticancer
metallodrugs
that
unfold
in plasma
(yelFigure
metallodrugs
that
unfold
in plasma
(yellow)
low)red
andblood
red blood
cells (red)
are critical
to establish
mechanism
of action,
as they
determine
and
cells (red)
are critical
to establish
theirtheir
mechanism
of action,
as they
determine
the
the degree of tumor damage/tumor shrinkage over days/weeks. Abbreviations: human serum albudegree of tumor damage/tumor shrinkage over days/weeks. Abbreviations: human serum albumin
min (HSA), red blood cells (RBC), hemoglobin (Hb), glutathione (GSH), lipid bilayer membrane
(HSA), red blood cells (RBC), hemoglobin (Hb), glutathione (GSH), lipid bilayer membrane (LBM),
(LBM), copper transporter 1 (CTR1).
copper transporter 1 (CTR1).
6.1. Stability of Metallodrugs/Novel Metal(loid) Complexes in Plasma
A low temporal stability of a novel metal complex in plasma will dramatically reduce
its probability
probability of
ofreaching
reachingthe
thecancer
cancertissue
tissueintact,
intact,and
and
thus,
increases
probability
of
thus,
increases
thethe
probability
of sesevere
toxic
side-effects
caused
by formed
the formed
degradation
products
Comvere
toxic
side-effects
thatthat
are are
caused
by the
degradation
products
[120].[120].
Compared
pared
toorganic
small organic
molecules,
this potential
much
more troublesome
for
to
small
molecules,
this potential
problemproblem
is muchismore
troublesome
for metallometallodrugs
since aof
rupture
of that
the bond
that
to its drugwill
framework
drugs
since a rupture
the bond
anchors
theanchors
metal tothe
its metal
drug framework
comprowill compromise
integrity
of the drug
molecule,
in turn
adversely
affecting
not only
mise
the integrity the
of the
drug molecule,
in turn
adversely
affecting
not only
the intended
the intended pharmacological
effect and
also contributing
its severe
adverse
pharmacological
effect and possibly
alsopossibly
contributing
to its severe to
adverse
side-effects.
Metallomics
tools,
which
involve
the
hyphenation
of
a
separation
technique
[e.g.,
capillary
side-effects. Metallomics tools, which involve the hyphenation of a separation technique
electrophoresis
size-exclusion
chromatography
high-/ultra-performance
liquid
[e.g., capillary (CE),
electrophoresis
(CE),
size-exclusion(SEC),
chromatography
(SEC), high-/ultrachromatography
(HPLC/UPLC)]
with(HPLC/UPLC)]
a metal-detectorwith
[e.g.,a inductively-coupled
performance liquid
chromatography
metal-detector [e.g.,plasma
inducmass
spectrometry
(ICP-MS),
inductively coupled
plasma
atomiccoupled
emissionplasma
spectroscopy
tively-coupled
plasma
mass spectrometry
(ICP-MS),
inductively
atomic
(ICP-AES)]
can provide much-needed
insight
intomuch-needed
the temporal stability
metallodrugs
in
emission spectroscopy
(ICP-AES)] can
provide
insight of
into
the temporal
serum
[124].
stability of metallodrugs in serum [124].
The anticancer drug cisplatin, for example, undergoes several bioinorganic chemistry
processes
processes in
in blood
blood plasma,
plasma, including
including hydrolysis
hydrolysis followed
followed by
by the
the binding
binding of
of the
the formed
formed
hydrolysis
hydrolysis products
products to
to plasma
plasmaproteins
proteins[76].
[76].These
Thesedynamic
dynamicbioinorganic
bioinorganicprocesses
processesgradugradally
thethe
plasma
concentration
of the
parent
drugdrug
that is
able
reach
the intended
uallydecrease
decrease
plasma
concentration
of the
parent
that
is to
able
to reach
the intumor
formed
hydrolysis
products
are likely
for its
tendedtissue
tumorintact,
tissue while
intact,the
while
the formed
hydrolysis
products
areresponsible
likely responsible
severe
side-effects
(Figure
4)
[76].
In
this
context,
it
is
important
to
point
out
that
the
for its severe side-effects (Figure 4) [76]. In this context, it is important to point outmere
that
observation
of a degradation
product of
a novel
complex
in bloodin
plasma
a
the mere observation
of a degradation
product
ofmetal
a novel
metal complex
blood using
plasma
metallomics
tool
cannot
provide
any
information
about
its
toxicity,
as
this
information
has
using a metallomics tool cannot provide any information about its toxicity, as this inforto
be established
using toxicological
assays. Theassays.
capability
of metallomics
tools to detect
mation
has to be established
using toxicological
The capability
of metallomics
tools
highly
cytotoxic
Pt
species
in
plasma
is
reminiscent
of
their
ability
to
identify
potentially
to detect highly cytotoxic Pt species in plasma is reminiscent of their ability to identify
toxic metal species in human serum from environmentally exposed people [125] and to
Inorganics 2022, 10, 200
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determine natural variations in the isotopic composition of CH3 Hg+ and Hg2+ in fish
tissue [126]. The application of SEC-ICP-AES has been particularly valuable to demonstrate
that 70% of the bimetallic Ti- and Au-containing complex Titanocref remains intact in
human plasma after incubation for 60 min at 37 ◦ C [63], while the Ti- and Au-containing
degradation products eluted bound to HSA. This comparatively novel metallomics tool has
also been successfully applied to compare in vitro the metabolism of pharmacologically
relevant doses of the FDA-approved platinum drugs cisplatin and carboplatin in human
blood plasma [76]. The results revealed a comparatively faster hydrolysis of cisplatin followed by the binding of the formed hydrolysis products to plasma proteins, predominantly
HSA, over a 24 h period compared to carboplatin. In addition, the hydrolysis products
that formed from each platinum drug appeared to bind to the same plasma proteins. Importantly, these temporal changes in the metabolism of cisplatin/carboplatin provided
an explanation for their considerably different toxic side-effects in patients [76] and the
different biodistribution of these platinum drugs to organs after treatment.
Conceptually related to the application of SEC-ICP-AES to probe the stability of metallodrugs and novel metal complexes in plasma, this metallomics tool has also allowed researchers
to visualize the deliberate modulation of the metabolism of cisplatin in human plasma by
D-methionine [127], N-acetyl-L-cysteine [128] and sodium thiosulfate [129], which revealed
that these SMW sulfur compounds can be used to ‘neutralize’ a highly toxic cisplatin hydrolysis product that is largely responsible for the severe side-effects of this Pt drug [130].
Thus, metallomics tools can be employed to obtain insight into the time-dependent in vitro
metabolism of novel metal complexes in blood plasma, which is useful not only to estimate
how much of the administered anticancer metal complex is likely to reach the cancer tissue
intact [12,63], but also to gain insight into the formation of degradation products that may
cause undesirable severe side-effects at the organ level [130,131].
6.2. Metallodrugs-/Novel-Metal(loid)-Complexes-Induced Rupture of RBCs
A novel-metal-entity-induced rupture of RBCs in the bloodstream results in the release
of Hb into plasma, which can cause severe toxic side-effects, such as potentially lifethreatening thrombotic effects and kidney toxicity [91]. Cisplatin, for example, is wellknown to perturb the integrity of cell membranes—resulting in the damage of chicken
RBCs [62]—which likely contributes to its severe side-effects in treated patients [56,123].
Based on the well-established metabolism of cisplatin in blood plasma [76], however, it
is unknown if the integrity of the RBC lipid bilayer membrane is perturbed by cisplatin
or its hydrolysis products. A recently developed metallomics tool can be employed to
analyze blood plasma (50 µL) for a hemoglobin–haptoglobin complex to estimate the RBC
rupture that is induced by a pharmacologically relevant dose of a metallodrug when added
to whole blood [132].
6.3. Assessment of the Selectivity of Metallodrugs/Novel Metal(loid) Complexes to Cancer Cells
The selectivity of a novel metal(loid) complex toward the intended cancer can be
assessed in cell-culture studies by measuring the IC50 value in cancer cells and healthy
cells (e.g., fibroblasts). The advent of single cell (sc) ICP-MS over the last couple of years
has demonstrated that it can—at least in principle—be employed to observe the uptake
of cisplatin into sensitive and resistant cancer cells [133]. Remarkably, this inherent capability offers the ability to probe the selectivity of novel metal(loid) complexes under
near-physiological conditions in vitro, with the caveat that, in the presence of the bloodstream, the same selectivity may not be obtainable in vivo.
Faced with the urgent need to accelerate more novel metal(loid) complexes that exhibit
the desired biological activity to clinical studies, the application of certain metallomics
tools (SEC-ICP-AES) can provide useful information about potentially adverse effects of
a metallodrug in the bloodstream (i.e., RBC rupture; degradation in plasma), while other
metallomics tools (scICP-MS) can allow for probing the selectivity of the metallodrug to
preferentially ‘hit’ cancer cells compared to healthy cells in vitro [133]. The analysis of a
Inorganics 2022, 10, 200
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set of novel metal(loid) complexes with different metallomics tools, therefore, offers the
prospect of identifying those that are stable in plasma, do not compromise the integrity
of RBCs (in blood) and exhibit selectivity toward cancer cells (Table 3). The complexes
that fulfill these criteria can then be forwarded to preclinical and clinical studies. While
knowledge about the mechanism of action of an anticancer drug at the biomolecular level
is unquestionably useful [134], it is not necessarily a priority when screening novel metal
complexes. Instead, their selective delivery to the tumor tissue should be the primary
focus [63,135].
7. Integrative Metallomics Studies
In order to make progress in terms of linking ‘molecular data’ of potentially toxic
metal(loid) species and cytotoxic metallodrugs with undesirable or desirable human health
effects, it is necessary to establish the complete sequence of bioinorganic chemical reactions
in various biological compartments of the bloodstream–organ system (i.e., plasma, RBCs
and organs) (Figures 3 and 4) (Table 3). With regard to the exposure of an organism to
a toxic metal(loid) species, one potential challenge is to measure an outcome in a target
organ (e.g., nutrient deficiency) [69,86,108], while it is comparatively easy to observe the
shrinkage/remission of a tumor after treatment with a metallodrug [136]. Our limited
understanding of the ‘molecular toxicology’ of toxic metal(loid) species and metallodrugs in
the bloodstream must be attributed to the fact that most studies are conducted using either
blood plasma or RBC lysate for practical reasons, since the shelf life of whole blood is rather
limited. This approach to addressing the bioinorganic chemistry in individual biological
compartments can intrinsically not answer the most crucial question of which specific
metal species will impinge on a toxicological target organ and/or tumor in the whole
organism. In a sense, this undesirable situation is somewhat reminiscent of the problem
that proteomics researchers faced who chose to study purified proteins in isolation for many
years without realizing that addressing the biological complexity requires one to study
protein–protein interactions to describe the events that unfold inside any given cell [137].
Since it is ultimately the flux of toxic metal(loid) substances that impinge on toxicological
target organs/tumors and determine the damage [detrimental in the context of toxic
metal(loid) species, but desirable in the context of metallodrugs], a better understanding of
the corresponding bioinorganic chemistry in the bloodstream will contribute to advancing
toxicology [108], ecotoxicology [138] and pharmacology [97]. Integrating the bioinorganic
mechanisms that unfold in the bloodstream with biomolecular uptake mechanisms that are
located at the organ surface [139] will inevitably advance human health, as these processes
play a crucial role in terms of a) causally linking human exposure to toxic metal(loids) to
disease and b) ultimately achieving ‘precision oncology’ [120]. Some metallomics tools,
such as X-ray-based spectroscopy, even offer the capability to probe deeper inside the
organ/tumor tissue to obtain information on the sub-cellular compartment that a specific
toxic metal(loid) or metallodrug targets in a healthy cell or cancer cell [140]. The innovative
applications of metallomics tools thus represent an essential first step in terms of unravelling
the potential pharmacology and the mechanism of action of novel metal(loid) complexes
to further advance the important role that integrated metallomics are destined to play in
health and disease [15].
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Table 3. Overview of studies which exemplify the usefulness of different metallomics tools to probe
the interaction of toxic metal(loid) substances with different biological fluids and/or cells.
Toxic Metal(loid)
Species in Biological
Fluid
Metallomics Tool(s)
Investigated Species
Obtained Information
Reference
SEC-ICP-AES
Cd2+
Cd2+ -driven displacement of Zn2+
from a Zn metalloprotein
[16]
SEC-ICP-AES
CH3 Hg+
formation of hCys-CH3 Hg+
complexes
[84]
SEC-ICP-AES and XAS
Hg2+ , CH3 Hg+ ,
CH3 CH2 Hg+ , Cd2+
formation of stable complexes of
Hg2+ , CH3 Hg+ and CH3 CH2 Hg+
with hemoglobin
[75]
SEC-ICP-AES and XAS
CH3 Hg+ and
(GS)2 AsSe-
formation of (GS)2 AsSe-HgCH3
[90]
Bile (in vivo)
XAS
injection of hamsters
with AsIII and SeIV
detection of (GS)2 AsSe-
[81]
Metallodrug in
Biological
Fluid/Compartment
Metallomics Tool
Investigated
Metallodrug
Obtained Information
Reference
SEC-ICP-AES
cisplatin and
carboplatin,
Titanocref
stability/degree of
hydrolysis/degradation
[76]
[63]
SEC-ICP-AES
cisplatin
formation of complexes between a
cisplatin-derived hydrolysis
product and thiosulfate
[129]
cisplatin
formation of complex
between a cisplatin-derived
hydrolysis product and
N-acetyl-L-cysteine
[128]
cisplatin
formation of complexes
between a cisplatin-derived
hydrolysis product and
D-methionine
[127]
SEC-ICP-AES
cisplatin
modulation of the metabolism of
cisplatin in serum of cancer
patients with human serum
albumin (HSA)
[141]
SEC-ICP-AES
(2,20 :60 2”-terpyridine)
platinum (II) complexes
binding to rabbit serum albumin
[131]
SEC-ICP-AES
cisplatin and NAMI-A
comparative metabolism
[142]
Whole blood (in vitro)
SEC-ICP-AES
SEC-GFAAS
no metallodrugs
investigated
dose-dependent effect of
metallodrug on RBC lysis
[99]
[132]
Healthy and cancer
cells (cell culture)
scICP-MS
cisplatin
selectivity of metallodrug
[133]
Blood plasma (in vitro)
Red blood cell cytosol
(in vitro)
SEC-ICP-AES
Blood plasma (in vitro)
SEC-ICP-AES
8. Conclusions
Throughout life, the dynamic flow of toxic metal(loid) species inevitably connects
every mammalian organism to the surface geochemistry of our home planet. Because
of the paucity of information about possible mechanistic links that functionally connect
environmental exposure to toxic metal(loid)s with adverse pregnancy outcomes [143],
neurodevelopment in children [144], adverse effects on organs [145] and human diseases
of unknown etiology [54,108], gaining insight into the underlying bioinorganic chemistry
Inorganics 2022, 10, 200
14 of 19
in the environment–bloodstream–organ system [146] is critical, especially given the rapidly
growing problem of dealing with electronic waste—of which we generate 53.5 million
metric t per year [147]. Elucidating this bioinorganic chemistry not only holds the prospect
of causally linking human environmental exposure to toxic metal(loid) species with the
etiology of neurodegenerative diseases including Alzheimer’s Disease [148] and to curb
emissions into the environment, but also to develop affordable, practical solutions [149].
Relatedly, the development of better anticancer metal-base drugs hinges on improving our
screening process of novel metal complexes to include events that unfold in the bloodstream
and, in turn, advance more drug candidates to preclinical studies [12]. The integration of
bioinorganic chemistry events in the blood plasma–RBC–organ system is therefore critical
to causally link human exposure to toxic metal(loid) species with diseases [150] and to help
discover the next generation of metallodrugs.
Funding: Funding for some of the studies cited in the article was provided by the Natural Sciences
and Engineering Research Council (NSERC) of Canada.
Institutional Review Board Statement: Studies that were conducted at the University of Calgary
were conducted in accordance with the Declaration of Helsinki, and approved by the Life & Environmental Sciences Animal Care Committee (LESACC) and the Conjoint Health Research Ethics Board
(CHREB).
Informed Consent Statement: Informed consent was obtained from all subjects that were involved
in studies conducted at the University of Calgary.
Data Availability Statement: The data presented in this study that were obtained at the University
of Calgary are available on request from the corresponding author.
Acknowledgments: Maryam Doroudian is supported by a grant from the Natural Sciences and
Engineering Research Council (NSERC) of Canada. We greatly appreciate one particular reviewer’s
feedback which helped to improve the overall quality and clarity of our manuscript.
Conflicts of Interest: The authors declare no conflict of interest.
References
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
Sousa, F.L.; Neunkirchen, S.; Allen, J.F.; Lane, N.; Martin, W.F. Lokiarcheon is hydrogen dependent. Nat. Microbiol. 2016, 16034,
1–3.
Li, J.J.; Pawitwar, S.S.; Rosen, B.P. The organoarsenical biocycle and the primordial antibiotic methylarsenite. Metallomics 2016, 8,
1047–1055. [CrossRef]
Vandal, G.M.; Fitzgerald, W.F.; Boutron, C.F.; Candelone, J.-P. Variations in mercury deposition to Antarctica over the past 34,000
years. Nature 1993, 362, 621–6623. [CrossRef]
McConnell, J.R.; Edwards, R. Coal burning leaves toxic heavy metal legacy in the Arctic. Proc. Natl. Acad. Sci. USA 2008, 105,
12140–12144. [CrossRef] [PubMed]
Izatt, R.M.; Izatt, S.R.; Bruening, R.L.; Izatt, N.E.; Moyer, B.A. Challenges to achievement of metal sustainability in our high-tech
society. Chem. Soc. Rev. 2014, 43, 2451–2475. [CrossRef]
Campbell, P.G.C.; Gailer, J. Effects of Non-essential Metal Releases on the Environment and Human Health. In Metal Sustainability:
Global Challenges, Consequences and Prospects; Izatt, R.M., Ed.; John Wiley & Sions Ltd.: Chichester, UK, 2016; pp. 221–252.
Llanos, E.J.; Leal, W.; Luu, D.H.; Jost, J.; Stadler, P.F.; Restrepo, G. Exploration of the chemical space and its three historical regimes.
Proc. Natl. Acad. Sci. USA 2019, 116, 12660–12665. [CrossRef]
Stern, F. Paul Ehrlich: The Founder of Chemotherapy. Angew. Chem. Int. Ed. 2004, 43, 4254–4261. [CrossRef]
Marzo, T.; La Mendola, D. Strike a balance: Between metals and non-metals, metalloids as a source of anit-infective agents.
Inorganics 2021, 9, 46. [CrossRef]
Bolli, R. William Harvey and the discovery of the circulation of the blood. Circul. Res. 2019, 124, 1300–1302.
Gailer, J. Reactive selenium metabolites as targets of toxic metals/metalloids in mammals: A molecular toxicological perspective.
Appl. Organometal. Chem. 2002, 16, 701–707. [CrossRef]
Sarpong-Kumankomah, S.; Gailer, J. Application of a novel metallomics tool to probe the fate of metal-based anticancer drugs in
blood plasma: Potential, challenges and prospects. Curr. Top. Med. Chem. 2021, 21, 48–58. [CrossRef]
Doroudian, M.; Gailer, J. Toxic metal(loid) species at the blood-organ interface. In Environmental and Biochemical Toxicology; Turner,
R.J., Gailer, J., Eds.; DeGruyter: Munich, Germany, 2022; Volume 1, p. 335.
Zheng, X.; Cheng, Y.; Wang, C. Global mapping of metalloproteomes. Biochemistry 2021, 60, 3507–3514. [CrossRef]
Inorganics 2022, 10, 200
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
38.
39.
40.
41.
15 of 19
Zhou, Y.; Li, H.; Sun, H. Metalloproteomics for biomedical research: Methodology and applications. Annu. Rev. Biochem. 2022, 91,
449–473. [CrossRef] [PubMed]
Gomez-Ariza, J.L.; Jahromi, E.Z.; Gonzalez-Fernandez, M.; Garcia-Barrera, T.; Gailer, J. Liquid chromatography-inductively
coupled plasma-based metallomic approaches to probe health-relevant interactions between xenobiotics and mammalian
organisms. Metallomics 2011, 3, 566–577. [CrossRef] [PubMed]
Theiner, S.; Schoeberl, A.; Schweikert, A.; Keppler, B.K.; Koellensperger, G. Mass spectrometry techniques for imaging and
detection of metallodrugs. Curr. Opin. Chem. Biol. 2021, 61, 123–134. [CrossRef]
Arruda, M.A.Z.; Jesus, J.R.D.; Blindauer, C.A.; Stewart, A.J. Speciomics as a concept involving chemical speciation and omics. J.
Proteom. 2022, 263, 104615. [CrossRef] [PubMed]
Pacyna, J.M. Monitoring and assessment of metal contaminants in the air. In Toxicology of Metals; Chang, L.W., Ed.; CRC Press:
Boca Raton, Florida, FL, USA, 1996; pp. 9–28.
Jonsson, S.; Andersson, A.; Nilsson, M.B.; Skyllberg, U.L.; Lundberg, E.; Schaefer, J.K.; Akerblom, S.; Bjoern, E. Terrestrial
dischanrges mediate trophic shifts and enhance methylmercury accumulation in estuarine biota. Sci. Adv. 2017, 3, e1601239.
[CrossRef] [PubMed]
Steffen, W.; Crutzen, P.J.; McNeill, J.R. The anthropocene: Are humans now overwhelming the great forces of nature? Ambio 2007,
36, 614–621. [CrossRef]
Kasozi, K.I.; Otim, E.O.; Ninsiima, H.I.; Zirintunda, G.; Tamale, A.; Ekou, J.; Musoke, G.H.; Muyinda, R.; Matama, K.; Mujinga, R.;
et al. An analysis of heavy metals contamination and estimating the daily intakes of vegetables in Uganda. Toxicol. Res. Appl.
2021, 5, 1–15. [CrossRef]
Borchers, A.; Teuber, S.S.; Keen, C.L.; Gershwin, M.E. Food safety. Clin. Rev. Allergy Immunol. 2010, 39, 95–141. [CrossRef]
Schartup, A.T.; Thackray, C.P.; Qureshi, A.; Dassuncao, C.; Gillespie, K.; Hanke, A.; Sunderland, E.M. Climate change and
overfishing increase neurotoxicant in marine predators. Nature 2019, 572, 648–650. [CrossRef] [PubMed]
Dufault, R.; LeBlanc, B.; Schnoll, R.; Cornett, C.; Schweitzer, L.; Wallinga, D.; Hightower, J.; Patrick, L.; Lukiw, W.J. Mercury from
chlor-alkali plants: Measured concentrations in food product sugar. Environ. Health 2009, 8, 1–6. [CrossRef] [PubMed]
McFarland, M.J.; Hauer, M.E.; Reuben, A. Half of US population exposed to adverse lead levels in early childhood. Proc. Natl.
Acad. Sci. USA 2022, 119, e2118631119. [CrossRef] [PubMed]
Guan, W.J.; Zheng, X.Y.; Chung, K.F.; Zhong, N.S. Impact of air pollution on the burden of chronic respiratory diseases in China:
Time for urgent action. Lancet 2016, 388, 1939–1951. [CrossRef]
Mills, N.L.; Donaldson, K.; Hadoke, P.W.; Boon, N.A.; MacNee, W.; Cassee, F.R.; Sandstroem, T.; Blomberg, A.; Newby, D.E.
Adverse cardionvascular effects of air pollution. Nat. Clin. Pract. Card. 2009, 6, 36–44. [CrossRef]
Steckling, N.; Tobollik, M.; Plass, D.; Hornberg, C.; Ericson, B.; Fuller, R.; Bose-O’Reilly, S. Global burden of disease of mercury
used in artisanal small-scale gold mining. Ann. Glob. Health 2017, 83, 234–247. [CrossRef]
Guney, M.; Zagury, G.J. Contamination by ten harmful elements in toys and children’s jewelry bought on the North American
market. Environ. Sci. Technol. 2013, 47, 5921–5930. [CrossRef]
Travasso, C. Skin whitening cream may contain mercury, and lipstick may contain chromium and nickel, Indian study shows.
Brit. Med. J. 2014, 348, g1330. [CrossRef]
Hamann, C.R.; Boonchai, W.; Wen, L.; Sakanashi, E.; Chu, C.-Y.; Hamann, K.; Hamann, C.P.; Sinniah, K.; Hamann, D.; Linda, L.
Spectrometric analysis of mercury content in 549 skin-lightening products: Is mercury toxicity a hidden global health hazard? J.
Am. Acad. Dermayol. 2013, 70, 281–287. [CrossRef]
Landrigan, P.J.; Fuller, R.; Acosta, N.J.R.; Adeyi, O.; Arnold, R.; Basu, N.; Balde, A.B.; Bertollini, R.; Bose-O’Reilly, S.; Boufford, J.I.;
et al. The Lancet commission on pollution and health. Lancet 2018, 391, 462–512. [CrossRef]
Trasande, L.; Liu, Y. Reducing the staggering costs of environmental disease in children, estimated at $76.6 billion in 2008. Health
Affair. 2011, 30, 863–870. [CrossRef] [PubMed]
North, A.E.; Sarpong-Kumankomah, S.; Bellavie, A.R.; White, W.M.; Gailer, J. Environmentally relevant concentrations of
aminopolycarboxylate chelating agents mobilize Cd from humic acid. J. Environ. Sci. 2017, 57, 249–257. [CrossRef] [PubMed]
Coulthard, T.J.; Macklin, M.G. Modeling long-term contamination in river systems from historical metal mining. Geology 2003, 31,
451–454. [CrossRef]
Pruvot, C.; Douay, F.; Herve, F.; Waterlot, C. Heavy metals in soil, crops and grass as a source of human exposure in the former
mining areas. J. Soils Sediments 2006, 6, 215–220. [CrossRef]
Lamborg, C.H.; Hammerschmidt, C.R.; Bowman, K.L.; Swarr, G.J.; Munson, K.M.; Ohnemus, D.C.; Lam, P.J.; Heimbuerger, L.-E.;
Rijkenberg, M.J.A.; Saito, M.A. A global ocean inventory of anthropogenic mercury based on water column measurements. Nature
2014, 512, 65–68. [CrossRef] [PubMed]
Streets, D.G.; Horowitz, H.M.; Jacob, D.J.; Lu, Z.; Levin, L.; ter Schure, A.F.H.; Sunderland, E.M. Total mercury released to the
environment by human activities. Environ. Sci. Technol. 2017, 51, 5969–5977. [CrossRef]
Ogunseitan, O.A. Mercury safety reform in the 21st centrury: Advancing the new framework for toxic substance control. Environ.
Sci. Policy Sustain. Dev. 2017, 59, 4–13. [CrossRef]
Hawkings, J.R.; Linhoff, B.S.; Wadham, J.L.; Stibal, M.; Lamborg, C.H.; Carling, G.T.; Lamarche-Gagnon, G.; Kohler, T.J.; Ward, R.;
Hendry, K.R.; et al. Large subglacial source of mercury from the southwestern margin of the Greenland Ice Sheet. Nat. Geosci.
2021, 14, 496–502. [CrossRef]
Inorganics 2022, 10, 200
42.
43.
44.
45.
46.
47.
48.
49.
50.
51.
52.
53.
54.
55.
56.
57.
58.
59.
60.
61.
62.
63.
64.
65.
66.
67.
68.
69.
70.
71.
16 of 19
Schaefer, H.R.; Dennis, S.; Fitzpatrick, S. Cadmium. Minimization strategies to reduce dietary exposure. J. Food Sci. 2020, 85,
260–267. [CrossRef]
Sebastian, A.; Prasad, M.N.V. Cadmium minimization in rice: A review. Agron. Sustain. Dev. 2014, 34, 155–173. [CrossRef]
Khan, S.; Cao, Q.; Zheng, Y.M.; Huang, Y.Z.; Zhu, Y.G. Health risks of heavy metals in contaminated soils and food crops irrigated
with wastewater in Beijing, China. Environ. Pollut. 2008, 152, 686–692. [CrossRef] [PubMed]
Cristol, D.A.; Brasso, R.L.; Condon, A.M.; Fovarque, R.E.; Friedman, S.L.; Hallinger, K.K.; Monroe, A.P.; White, A.E. The
movement of aquatic mercury through terrestrial food webs. Science 2008, 320, 335. [CrossRef] [PubMed]
Obrist, D.; Agnan, Y.; Jiskra, M.; Olson, C.L.; Colegrove, D.P.; Hueber, J.; Morre, C.W.; Sonke, J.E.; Helmig, D. Tundra uptake of
atmospheric elemental mercury drives Arctic mercury pollution. Nature 2017, 547, 201–204. [CrossRef] [PubMed]
Nyanza, E.C.; Bernier, F.P.; Martin, J.W.; Manyama, M.; Hatfield, J.; Dewey, D. Effetcs of prenatal expsoure and co-exposure to
metallic or metalloid elements on early infant neurodevelopment outcomes in areas with small-scale gold mining activities in
Northern Tanzania. Environ. Int. 2021, 149, 106104. [CrossRef] [PubMed]
Mitchell, E.; Frisbie, S.; Sarkar, B. Exposure to multiple metals from groundwater-a global crisis: Geology, climate change, health
effects, testing, and mitigation. Metallomics 2011, 3, 874–908. [CrossRef]
Sanchez-Rodas, D.; Sanchez de la Campa, A.; Martinez, M.M. The role of metalloids (As, Sb) in airborne particulate matter related
to air pollution. In Environmental and Biochemical Toxicology; Turner, R.J., Gailer, J., Eds.; DeGruyetr: Munich, Germany, 2022; pp.
169–189.
Turner, R.J. Toxicity of nanomaterials. In Environmental and Biochemical Toxicology; DeGruyter: Munich, Germany, 2022; pp.
221–247.
Rappaport, S.M. Discovering environmental causes of disease. J. Epidemiol. Community Health 2012, 66, 99–102. [CrossRef]
Weiss, B.; Clarkson, T.W.; Simon, W. Silent latency period in methylmercury poisoning and in neurodegenerative disease. Environ.
Health Perspect. 2002, 110, 851–854. [CrossRef]
Sturla, S.J.; Boobis, A.R.; Fitzgerald, R.E.; Hoeng, J.; Kavlock, R.J.; Schirmer, K.; Whelan, M.; Wilks, M.F.; Peitsch, M.C. Systems
toxicology: From basic research to risk assessment. Chem. Res. Toxicol. 2014, 27, 314–329. [CrossRef]
Marth, J.D. A unified vision of the building blocks of life. Nature Cell. Biol. 2008, 10, 1015–1016. [CrossRef]
Rosenberg, B.; Van Camp, L.; Krigas, T. Inhibition of cell division in Escherichia coli by electrolysis products from a platinum
electrode. Nature 1965, 205, 698–699. [CrossRef]
Oun, R.; Moussa, Y.E.; Wheate, N.J. The side effetcs of platinum-based chemotherapy drugs: A review for chemists. Dalton Trans.
2018, 47, 6645–6653. [CrossRef] [PubMed]
Mjos, K.D.; Orvig, C. Metallodrugs in medicinal inorganic chemistry. Chem. Rev. 2014, 114, 4540–4563. [CrossRef] [PubMed]
Sooriyaarachchi, M.; Morris, T.T.; Gailer, J. Advanced LC-analysis of human plasma for metallodrug metabolites. Drug Discov.
Today Technol. 2015, 16, e24–e30. [CrossRef] [PubMed]
Hambley, T.W. Metal-based therapeutics. Science 2007, 318, 1392–1393. [CrossRef] [PubMed]
Poirier, A.E.; Ruan, Y.; Walter, S.D.; Franco, E.L.; Villeneuve, P.J.; King, W.D.; Volesky, K.D.; O’Sullivan, D.E.; Friedenreich, C.M.;
Brenner, D.R. The future burden of cancer in Canada: Long-term cancer incidence projections. Cancer Epidemiol. 2019, 59, 199–207.
[CrossRef]
Casini, A.V.A.; Meier-Menches, S.M. Metal-Based Anticancer Agents; Royal Society of Chemistry: London, UK, 2019.
Kutwin, M.; Sawosz, E.; Jaworski, S.; Kurantowicz, N.; Strojny, B.; Chwalibog, A. Structural damage of chicken red blood cells
exposed to platinum nanoparticles and cisplatin. Nanoscale Res. Lett. 2014, 9, 257. [CrossRef]
Sarpong-Kumankomah, S.; Contel, M.; Gailer, J. SEC hyphenated to a multielement-specific detector unravels the degradation
pathway of a bimetallic anticancer complex in human plasma. J. Chromatogr. B 2020, 1145, 122093. [CrossRef]
Gandin, V.; Ceresca, C.; Esposito, G.; Indraccolo, S.; Porchia, M.; Tisano, F.; Santini, C.; Pellei, M.; Marzano, C. Therapeutic
potential of the phosphino Cu(I) complex (HydroCuP) in the treatment of solid tumors. Sci. Rep. 2017, 7, 13936. [CrossRef]
Marcus, W.L.; Rispin, A.S. Threshold carcinogenicity using arsenic as an example. In Advances in Modern Environmental Toxicology;
Cothern, C.R., Mehlmans, M.A., Marcus, W.L., Eds.; Princeton Scientific Publishing Company, Inc: Princeton, NJ, USA, 1988;
Volume 15, pp. 133–158.
Kitchin, K.T. The role of protein binding of trivalent arsenicals in arsenic carcinogenesis and toxicity. J. Inorg. Biochem. 2008, 102,
532–539. [CrossRef]
Waisberg, M.; Joseph, P.; Hale, B.; Beyersmann, D. Molecular and cellular mechanisms of cadmium carcinogenesis. Toxicology
2003, 192, 95–117. [CrossRef]
Anderson, N.L.; Anderson, N.G. The human plasma proteome: History, character, and diagnostic prospects. Mol. Cell. Proteom.
2002, 1, 845–867. [CrossRef] [PubMed]
Bridle, T.G.; Kumarathasan, P.; Gailer, J. Toxic metal species and ‘endogenous’ metalloproteins at the blood-organ interface:
Analytical and bioinorganic aspects. Molecules 2021, 26, 3408. [CrossRef] [PubMed]
Righetti, P.G.; Boschetti, E. The Proteominer and the fortyniners: Searching for gold nuggest in the proteomic arena. Mass Spec.
Rev. 2008, 27, 596–608. [CrossRef] [PubMed]
Gailer, J. Metal species in biology: Bottom-up and top-down LC approaches in applied toxicological research. ISRN Chromatography
2013, 2013, 21. [CrossRef]
Inorganics 2022, 10, 200
72.
73.
74.
75.
76.
77.
78.
79.
80.
81.
82.
83.
84.
85.
86.
87.
88.
89.
90.
91.
92.
93.
94.
95.
96.
97.
17 of 19
Sarpong-Kumankomah, S.; Miller, K.; Gailer, J. Biological chemistry of toxic metals and metalloids, such as arsenic, cadmium and
mercury. In Encyclopedia of Analytical Chemistry; John Wiley & Sons, Ltd.: Hoboken, NJ, USA, 2020; pp. 2006–2020.
Gailer, J. Arsenic-selenium and mercury-selenium bonds in biology. Coord. Chem. Rev. 2007, 251, 234–254. [CrossRef]
Kerek, E.; Hassanin, M.; Prenner, E.J. Inorganic mercury and cadmium induce rigidity in eukaryotic lipid extracts while mercury
also ruptures red blood cells. Biochim. Biophys. Acta 2018, 1860, 710–717. [CrossRef]
Gibson, M.A.; Sarpong-Kumankomah, S.; Nehzati, S.; George, G.N.; Gailer, J. Remarkable differences in the biochemical fate of
Cd2+ , Hg2+ , CH3 Hg+ and thimerosal in red blood cell lysate. Metallomics 2017, 9, 1060–1072. [CrossRef]
Sooriyaarachchi, M.; Narendran, A.; Gailer, J. Comparative hydrolysis and plasma binding of cis-platin and carboplatin in human
plasma in vitro. Metallomics 2011, 3, 49–55. [CrossRef]
Manley, S.A.; Gailer, J. Analysis of the plasma metalloproteome by SEC-ICP-AES: Bridging proteomics and metabolomics. Expert.
Rev. Proteom. 2009, 6, 251–265. [CrossRef]
Gailer, J.; George, G.N.; Pickering, I.J.; Prince, R.C.; Ringwald, S.C.; Pemberton, J.E.; Glass, R.S.; Younis, H.S.; DeYoung, D.W.;
Aposhian, H.V. A metabolic link between arsenite and selenite: The Seleno-bis(S-glutathionyl) Arsinium Ion. J. Am. Chem. Soc.
2000, 122, 4637–4639. [CrossRef]
Gailer, J.; George, G.N.; Pickering, I.J.; Madden, S.; Prince, R.C.; Yu, E.Y.; Denton, M.B.; Younis, H.S.; Aposhian, H.V. Structural
basis of the antagonism between inorganic mercury and selenium in mammals. Chem. Res. Toxicol. 2000, 13, 1135–1142. [CrossRef]
[PubMed]
Manley, S.A.; George, G.N.; Pickering, I.J.; Glass, R.S.; Prenner, E.J.; Yamdagni, R.; Wu, Q.; Gailer, J. The seleno bis (S-glutathionyl)
arsinium ion is assembled in erythrocyte lysate. Chem. Res. Toxicol. 2006, 19, 601–607. [CrossRef] [PubMed]
Ponomarenko, O.; LaPorte, P.F.; Singh, S.P.; Langan, G.; Fleming, D.E.B.; Spallholz, J.; Alauddin, M.; Ahsan, H.; Ahmed, S.;
Gailer, J.; et al. Selenium-mediated arsenic excretion in mammals: A synchrotron-based study of whole-body distribution and
tissue-specific chemistry. Metallomics 2017, 9, 1585–1595. [CrossRef] [PubMed]
Gailer, J.; Ruprecht, L.; Reitmeir, P.; Benker, B.; Schramel, P. Mobilization of exogenous and endogenous selenium to bile after the
intravenous administration of environmentally relevant doses of arsenite to rabbits. Appl. Organometal. Chem. 2004, 18, 670–675.
[CrossRef]
Maret, W.; Moulis, J.M. The bioinorganic chemistry of cadmium in the context of its toxicity. In Cadmium: From Toxicity to
Essentiality, Metal Ions in Life Sciences; Sigel, A.S.H., Sigel, R.K.O., Eds.; Springer Science+Business Media Dordrecht: Basel,
Switzerland, 2013; Volume 25, pp. 1–29.
Bridle, T.G.; Doroudian, M.; White, W.; Gailer, J. Physiologically relevant hCys concentrations mobilize MeHg from rabbit serum
albumin to form MeHg-hCys complexes. Metallomics 2022, 14, mfac010. [CrossRef] [PubMed]
Wang, Y.; Fang, J.; Leonard, S.S.; Rao, K.M.K. Cadmium inhibits the electron transfer chain and induces reactive oxygen species.
Free Rad. Biol. Med. 2004, 36, 1434–1443. [CrossRef]
Sarpong-Kumankomah, S.; Gibson, M.A.; Gailer, J. Organ damage by toxic metals is critically determined by the bloodstream.
Coord. Chem. Rev. 2018, 374, 376–386. [CrossRef]
Thijssen, S.; Maringwa, J.; Faes, C.; Lambrichts, I.; Van Kerkhove, E. Chronic exposure of mice to environmentally relevant, low
doses of cadmium leads to early renal damage, not predicted by blood or urine cadmium levels. Toxicology 2007, 229, 145–156.
[CrossRef]
Bakir, F.; Damluji, S.F.; Amin-Zaki, L.; Murtafdha, M.; Khalidi, A.; Al-Rawi, N.Y.; Tikriti, S.; Dhahir, H.I.; Clarkson, T.W.; Smith,
J.C.; et al. Methylmercury poisoning in Iraq. Science 1973, 181, 230–241. [CrossRef]
Nordberg, G.F. Historical perspectives on cadmium toxicity. Toxicol. Appl. Pharmacol. 2009, 238, 192–200. [CrossRef]
Korbas, M.; Percy, A.J.; Gailer, J.; George, G.N. A possible molecular link between the toxicological effects of arsenic, selenium
and methylmercury: Methylmercury(II) seleno bis (S-glutathionyl) arsenic(III). J. Biol. Inorg. Chem. 2008, 13, 461–470. [CrossRef]
[PubMed]
Rother, R.P.; Bell, L.; Hillmen, P.; Gladwin, M.T. The clinical sequelae of intravascular hemolysis and extracellular plasma
hemoglobin. J. Am. Med. Assoc. 2005, 293, 1653–1662. [CrossRef] [PubMed]
Kostic, M.M.; Ognjanovic, B.; Dimitrijevic, S.; Zikic, R.V.; Stajn, A.; Rosic, G.L.; Zivkovic, R.V. Cadmium-induced changes of
antioxidant and metabolic status in red blood cells of rats: In vivo effects. Eur. J. Haematol. 1993, 51, 86–92. [CrossRef] [PubMed]
Horiguchi, H.; Oguma, E.; Kayama, F. Cadmium induces anaemia through interdependent progress of hemolysis, body iron
accumulation, and insufficient erythropoietin production in rats. Toxicol. Sci. 2011, 122, 198–210. [CrossRef]
Manley, S.A.; Byrns, S.; Lyon, A.W.; Brown, P.; Gailer, J. Simultaneous Cu-, Fe-, and Zn-specific detection of metalloproteins
contained in rabbit plasma by size-exclusion chromatography-inductively coupled plasma atomic emission spectroscopy. J. Biol.
Inorg. Chem. 2009, 14, 61–74. [CrossRef] [PubMed]
Sarpong-Kumankomah, S.; Knox, K.B.; Kelly, M.E.; Hunter, G.; Popescu, B.; Nichol, H.; Kopciuk, K.; Ntanda, H.; Gailer, J.
Quantification of human plasma metalloproteins in multiple sclerosis, ischemic stroke and health controls reveals an association
of haptoglobin-hemoglobin complexes with age. PLoS ONE 2022, 17, e0262160. [CrossRef]
Suzuki, K.T.; Sunaga, H.; Kobayashi, E.; Shimojo, N. Mercaptoalbumin as a selective cadmium-binding protein in rat serum.
Toxicol. Appl. Pharmacol. 1986, 86, 466–473. [CrossRef]
Massai, L.; Pratesi, A.; Gailer, J.; Marzo, T.; Messori, L. The cisplatin/serum albumin systen: A reappraisal. Inorg. Chim. Acta 2019,
495, 118983. [CrossRef]
Inorganics 2022, 10, 200
98.
99.
100.
101.
102.
103.
104.
105.
106.
107.
108.
109.
110.
111.
112.
113.
114.
115.
116.
117.
118.
119.
120.
121.
122.
123.
124.
18 of 19
de Magalhanes Silva, M.; de Araujo Dantas, M.D.; de Sila Filho, R.C.; dos Santos Sales, M.V.; de Almeida Xavier, J.; Leite, A.C.R.;
Goulart, M.O.F.; Grillo, L.A.M.; de Barros, W.A.; de Fatima, A.; et al. Toxicity of thimerosal in biological systems: Conformational
changes in human hemoglobin, decrease of oxygen binding, increase of protein glycation and amyloid formation. Intern. J. Biol.
Macromol. 2020, 154, 661–671. [CrossRef]
Sarpong-Kumankomah, S.; Gailer, J. Identification of a haptoglobin-hemoglobin complex in human blood plasma. J. Inorg.
Biochem. 2019, 201, 110802. [CrossRef]
Muckenthaler, M.U.; Rivella, S.; Hentze, M.W.; Galy, B. A red carpet for iron metabolism. Cell 2017, 168, 344–361. [CrossRef]
[PubMed]
Gebicka, L.; Krych-Madej, J. The role of catalases in the prevention/promotion of oxidative stress. J. Inorg. Biochem. 2019, 197,
110699. [CrossRef] [PubMed]
Supuran, C.T. Structure and function of carbonic anhydrases. Biochem. J. 2016, 473, 2023–2032. [CrossRef] [PubMed]
Ordonez, Y.N.; Montes-Bayon, M.; Blanco-Gonzalez, E.; Sanz-Medel, A. Quantitative analysis and simultaneous activity measurements of Cu, Zn-superoxide dismutase in red blood cells by HPLC-ICPMS. Anal. Chem. 2010, 82, 2387–2394. [CrossRef]
[PubMed]
Shin, S.-Y.; Fauman, E.B.; Petersen, A.-K.; Krumsiek, J.; Santos, R.; Huang, J.; Arnold, M.; Erte, I.; Forgetta, V.; Yang, T.-P.; et al. An
atlas of genetic influences on human blood metabolites. Nat. Genet. 2014, 46, 543–550. [CrossRef]
Thomas, D.J.; Smith, J.C. Effects of coadministered low-molecular weight thiol compounds on short-term distribution of
methylmercury in the rat. Toxicol. Appl. Pharmacol. 1982, 62, 104–110. [CrossRef]
Simmons-Wills, T.A.; Koh, A.S.; Clarkson, T.W. Transport of a neurotoxicant by molecualr mimicry: The methylmercury-Lcysteine complex is a substrate for human L-type large neutral amino acid transporter (LAT) 1 and LAT 2. Biochem. J. 2002, 367,
239–246. [CrossRef]
Jakubowski, H. Homocysteine modification in protein structure/function and human disease. Physiol. Rev. 2019, 99, 555–604.
[CrossRef]
Hill, A.; Gailer, J. Linking molecular targets of Cd in the bloodstream to organ-based adverse health effects. J. Inorg, Biochem. 2021,
216, 111279. [CrossRef]
Costa, L.G.; Aschner, M.; Vitalone, A.; Syversen, T.; Soldin, O.P. Developmental neuropathology of environmental agents. Annu.
Rev. Pharmacol. Toxicol. 2004, 44, 87–110. [CrossRef]
Kelland, L. The resurgence of platinum-based cancer chemotherapy. Nat. Rev. Cancer 2007, 7, 573–584. [CrossRef] [PubMed]
Bruno, P.M.; Liu, Y.; Park, G.Y.; Murai, J.; Koch, C.E.; Eisen, T.J.; Pritchard, J.R.; Pommier, Y.; Lippard, S.J.; Hemann, M.T. A subset
of platinum-containing chemotherapeutic agents kill cells by inducing ribosome biogenesis stress rather that by engaging a DNA
damage response. Nat. Med. 2017, 23, 461–471. [CrossRef] [PubMed]
Santini, C.; Pellei, M.; Gandin, V.; Porchia, M.; Tisato, F.; Marzano, C. Advances in copper complexes as anticancer agents. Chem.
Rev. 2014, 114, 815–862. [CrossRef] [PubMed]
Mu, C.; Prosser, K.E.; Harrypersad, S.; MacNeil, G.A.; Panchmatia, R.; Thompson, J.R.; Sinha, S.; Warren, J.J.; Walsby, C.J. Activation by oxidation: Ferrocene-functionalized Ru(II)-arene complexes with anticancer, antibacterial, and antioxidant properties.
Inorg. Chem. 2018, 57, 15247–15261. [CrossRef]
Morrison, C.N.; Prosser, K.E.; Stokes, R.W.; Cordes, A.; Metzler-Nolte, N.; Cohen, S.M. Expanding medicinal chemistry into 3D
space: Metallofragments as 3D scaffolds for fragment-based drug discovery. Chem. Sci. 2020, 11, 1216–1225. [CrossRef]
Prosser, K.E.; Stokes, R.W.; Cohen, S.M. Evaluation of 3-dimensionality in approved and experimental drug space. ACS Med.
Chem. Lett. 2020, 11, 1292–1298. [CrossRef]
Frei, A.; Zuegg, J.; Elliott, A.G.; Baker, M.; Braese, S.; Brown, C.; Chen, F.; Dowson, C.G.; Dujardin, G.; Jung, N.; et al. Metal
complexes as a promising source for new antibiotics. Chem. Sci. 2020, 11, 2627–2639. [CrossRef]
Kenny, R.G.; Marmion, C.J. Toward multi-targeted platinum and ruthenium drugs-a new paradigm in cancer drug treatment
regimens? Chem. Rev. 2019, 119, 1058–1137. [CrossRef]
Fronik, P.; Poetsch, I.; Kastner, A.; Mendrina, T.; Hager, S.; Hohenwallner, K.; Schueffl, H.; Herndler-Brandstetter, D.; Koellensperger, G.; Rampler, E.; et al. Structure-activity relationships of triple-action platinum(IV) prodrugs with albumin-binding
properties and immunomodulating ligands. J. Med. Chem. 2021, 64, 12132–12151. [CrossRef]
Englinger, B.; Pirker, C.; Heffeter, P.; Terenzi, A.; Kowol, C.R.; Keppler, B.K.; Berger, W. Metal drugs and the anticancer immune
response. Chem. Rev. 2019, 119, 1519–1624. [CrossRef]
Hambley, T.W. Transporter and protease mediated delivery of platinum complexes for precision oncology. J. Biol. Inorg. Chem.
2019, 24, 457–466. [CrossRef] [PubMed]
Bruijnincx, P.C.A.; Sadler, P.J. New trends for metal complexes with anticancer activity. Curr. Opin. Chem. Biol. 2008, 12, 197–206.
[CrossRef] [PubMed]
Moretto, J.; Chauffert, B.; Ghiringhelli, F.; Aldrich-Wright, J.R.; Bouyer, F. Discrepancy between in vitro and in vivo antitumor
effect of a new platinum(II) metallointercalator. Invest. New Drugs 2011, 29, 1164–1176. [CrossRef] [PubMed]
Mandal, R.; Kalke, R.; Li, X.-F. Interaction of oxaliplatin, cisplatin, and carboplatin with hemoglobin and the resulting release of a
heme group. Chem. Res. Toxicol. 2004, 17, 1391–1397. [CrossRef] [PubMed]
Timerbaev, A.R.; Hartinger, C.G.; Aleksenko, S.S.; Keppler, B.K. Interactions of antitumor metallodrugs with serum proteins:
Advances in characterization using modern analytical methodology. Chem. Rev. 2006, 106, 2224–2248. [CrossRef]
Inorganics 2022, 10, 200
19 of 19
125. Levine, K.E.; Young, D.J.; Afton, S.E.; Harrington, J.M.; Essader, A.S.; Weber, F.X.; Fernando, R.A.; Thayer, K.; Hatch, E.E.;
Robinson, V.C.; et al. Development, validation, and application of an ultra-performance liquid chromatography-sector field
inductively coupled plasma mass spectrometry method for simultaneous determination of six organotin compounds in human
serum. Talanta 2015, 140, 115–121. [CrossRef]
126. Entwisle, J.; Malinovsky, D.; Dunn, P.J.H.; Goenaga-Infante, H. Hg isotope ratio measurements of methylmercury in fish tissues
using HPLC with off line cold vapour generation MC-ICPMS. J. Anal. At. Spetcrom. 2018, 33, 1645–1654. [CrossRef]
127. Sooriyaarachchi, M.; Narendran, A.; White, W.H.; Gailer, J. Chemoprotection by D-methionine against cis-platin-induced
side-effects: Insight from in vitro studies using human plasma. Metallomics 2014, 6, 532–541. [CrossRef]
128. Sooriyaarachchi, M.; Narendran, A.; Gailer, J. N-acetyl-L-cysteine modulates the metabolism of cis-platin in human plasma
in vitro. Metallomics 2013, 5, 197–207. [CrossRef]
129. Sooriyaarachchi, M.; Narendran, A.; Gailer, J. The effect of sodium thiosulfate on the metabolism of cis-platin in human plasma
in vitro. Metallomics 2012, 4, 960–967. [CrossRef]
130. Sooriyaarachchi, M.; George, G.N.; Pickering, I.J.; Narendran, A.; Gailer, J. Tuning the metabolism of the anticancer drug cisplatin
with chemoprotective agents to improve its safety and efficacy. Metallomics 2016, 8, 1170–1176. [CrossRef] [PubMed]
131. Harper, B.W.J.; Morris, T.T.; Gailer, J.; Aldrich-Wright, J.R. Probing the interaction of bisintercalating (2,20 :60 200 )platinum(II)
complexes with glutathione and rabbit plasma. J. Inorg. Biochem. 2016, 163, 95–102. [CrossRef] [PubMed]
132. Miller, K.; Sarpong-Kumankomah, S.; Egorov, A.; Gailer, J. Sample preparation of blood plasma enables baseline separation of
iron metalloproteins by SEC-GFAAS. J. Chromatogr. B 2020, 1147, 122147. [CrossRef] [PubMed]
133. Corte Rodriguez, M.; Alvarez-Fernandez Garcia, R.; Blanco, E.; Bettmer, J.; Montes-Bayon, M. Quantitative evaluation of cisplatin
uptake in sensitive and resistant individual cells by single-cell ICP-MS (sc-ICP-MS). Anal. Chem. 2017, 89, 11491–11497. [CrossRef]
134. Temaj, G.; Chichiarelli, S.; Eufemi, M.; Altieri, F.; Hadziselimovic, R.; Farooki, A.A.; Yaylim, I.; Saso, L. Ribosome-directed
therapies in cancer. Biomedicines 2022, 10, 2088. [CrossRef]
135. He, L.; Chen, T.; You, Y.; Hu, H.; Zheng, W.; Kwong, W.-L.; Zou, T.; Che, C.-M. A cabcer-targeted nanosystem for delivery of
Gold(III) complexes: Enhanced selectivity and apoptosis-inducing efficacy of a gold (III) porphyrin complex. Angew. Chem. Int.
Ed. 2014, 53, 12532–12536.
136. Soignet, S.L.; Maslak, P.; Wang, Z.-G.; Jhanwar, S.; Calleja, E.; Dardashti, L.J.; Corso, D.; DeBlasio, A.; Gabrilove, J.; Scheinberg,
D.A.; et al. Complete remission after treatment of acute promyelocytic leukemia with arsenic trioxide. N. Engl. J. Med. 1998, 339,
1341–1348. [CrossRef]
137. Gierasch, L.M.; Gershenson, A. Post-reductionist protein science, or putting Humpty Dumpty back together again. Nat. Chem.
Biol. 2009, 5, 774–777. [CrossRef]
138. Mani, U.; Prasad, A.K.; Kumar, V.S.; Lal, K.; Kanojia, R.; Chaudhari, B.P.; Murthy, R.C. Effect of fly ash on biochemical and
histomorphological changes in rat liver. Ecotoxicol. Environ. Saf. 2007, 68, 126–133. [CrossRef]
139. Puris, E.; Gynther, M.; Auriola, S.; Huttunen, K.M. L-type amino acid transporter I as a target for drug delivery. Pharm. Res. 2020,
37, 88. [CrossRef]
140. Xiong, X.; Liu, L.-Y.; Mao, Z.-W.; Zou, T. Approaches towards understanding the mechanism-of-action of metallodrugs. Coord.
Chem. Rev. 2022, 453, 214311. [CrossRef]
141. Morris, T.T.; Ruan, Y.; Lewis, V.A.; Narendran, A.; Gailer, J. Fortification of blood plasma from cancer patients with human
serum albumin decreases the concentration of cis-platin derived toxic hydrolysis products in vitro. Metallomics 2014, 6, 2034–2041.
[CrossRef] [PubMed]
142. Sooriyaarachchi, M.; Wedding, J.A.; Harris, H.H.; Gailer, J. Simultaneous observation of the metabolism of cisplatin and NAMI-A
in human plasma in vitro by SEC-ICP-AES. Metallomics 2014, 19, 1049–1053. [CrossRef] [PubMed]
143. Au, F.; Bielecki, A.; Blais, E.; Fisher, M.; Cakmak, S.; Basak, A.; Gomes, J.; Arbuckle, T.E.; Fraser, W.D.; Vincent, R.; et al. Blood
metal levels and third trimester maternal plasma matrix metalloproteinases (MMPs). Chemosphere 2016, 159, 506–515. [CrossRef]
[PubMed]
144. Grandjean, P.; Landrigan, P.J. Developmental neurotoxicity of industrial chemicals. Lancet 2006, 368, 2167–2178. [CrossRef]
145. Orr, S.E.; Bridges, C.C. Chronic kideny disease and exposure to nephrotoxic metals. Int. J. Mol. Sci. 2017, 18, 1039. [CrossRef]
[PubMed]
146. Nogara, P.A.; Oliveira, C.S.; Schmitz, G.L.; Piquini, P.C.; Farina, M.; Aschner, M.; Rocha, J.B.T. Methylmercury’s chemistry: From
the environment to the mammalian brain. Biochim. Biophys. Acta Gen. Subj. 2019, 1863, 129284. [CrossRef]
147. Saha, A.L.; Kumar, V.; Tiwari, J.; Rawat, S.; Singh, J.; Bauddh, K. Electronic waste and their leachates impact on human health and
environment: Global ecological threat and management. Environ. Technol. Innov. 2021, 24, 102049.
148. Bjorklund, G.; Tinkov, A.A.; Dadar, M.; Rahman, M.M.; Chirumbolo, S.; Skalny, A.V.; Skalnaya, M.G.; Haley, B.E.; Ajsuvakova,
O.P.; Aaseth, J. Insights into the potential role of mercury in Alzheimer’s disease. J. Mol. Neurosci. 2019, 67, 511–533. [CrossRef]
149. Chapman, L.; Chan, H.M. The influence of nutrition on methyl mercury intoxication. Environ. Health Perspect. 2000, 108, 29–56.
150. Rossignol, D.A.; Genius, S.J.; Frye, R.E. Environmental toxicants and autism spetrum disorders: A systematic review. Transl.
Psychiatry 2014, 4, e360. [CrossRef] [PubMed]
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Isidro Martínez Mira
University of Alicante / Universidad de Alicante
Angel Berenguer
University of Alicante / Universidad de Alicante
SIVA UMAPATHY
Indian Institute of Science
Michitaka Ohtaki
Kyushu University
