Metabolism of Xenobiotics

Metabolism of Xenobiotics
INTRODUCTION
• Human are subjected to exposure to various foreign chemicals
(xenobiotics) : drugs, food additives, pollutants, etc.
• Understanding how xenobiotics are handled at the cellular level is

important in learning how to cope with the chemical onslaught, and
thus helping to preserve the environment.
• For example, to modify microorganisms by introducing genes that

encode various enzymes involved in metabolizing specific
xenobiotics to harmless products.
• These modified organisms will then be used to help dispose of

various pollutants that contaminate our planet.
BIOMEDICAL IMPORTANCE
• Knowledge of the metabolism of xenobiotics is basic to a rational

understanding of :
- Pharmacology and therapeutics
- Pharmacy
- Toxicology,
- Management of cancer
- Drug addiction
BIOMEDICAL IMPORTANCE
Major Categories of Xenobiotics
• Drugs
• Food constituents
• Food additives
• Chemicals of abuse (ethanol, coffee, tobacco..etc)
• Agrochemicals (fertilizers, insecticides,
herbicides…etc)
• Industrial chemicals (solvents, dyes, monomers,
polymers..etc)
• Pollutants
• In phase 1, the major reaction involved is hydroxylation, catalyzed
by members of a class of enzymes referred to as
monooxygenases or Cytochrome P450
(Martin Klingenberg ,1958)
• Hydroxylation may terminate the action of a drug, though this is

not always the case.
• In addition to hydroxylation, these enzymes catalyze a wide range

of reactions, including those involving:
- deamination, dehalogenation, desulfuration,
- epoxidation, peroxygenation, and reduction.
• Reactions involving hydrolysis (eg, by esterases) and certain

other non-P450-catalyzed reactions also occur in phase 1.
In Phase 2
• The hydroxylated or other compounds produced in phase 1 are

converted by specific enzymes to various polar metabolites by
conjugation with:
- glucuronic acid,
- sulfate,
- acetate,
- glutathione, or
- certain amino acids, or
- by methylation.
• The overall purpose of the two phases of metabolism of

xenobiotics is to increase their water solubility (polarity) and
thus excretion from the body.
Specific families of phase II xenobiotic-
metabolizing enzymes :
• UDP-glucuronosyltransferases (UGTs),
• Sulfotransferases (STs),
• N-acetyltransferases (arylamine N-acetytransferase; NAT), and
• Glutathione S-transferases (GST) and
• Methyltransferases (MT)
• In certain cases, phase 1 convert xenobiotics from inactive to
biologically active compounds. In these instances, the original
xenobiotics are referred to as prodrugs or procarcinogens.
• In other cases, additional phase 1 reactions (eg, further hydroxylation

reactions) convert the active compounds to less active or inactive
forms prior to conjugation.
• In yet other cases, it is the conjugation reactions themselves that

convert the active products of phase 1 reactions to less active or
inactive species, which are subsequently excreted in the urine or bile.
• In a very few cases, conjugation may actually increase the biologic

activity of a xenobiotic.
Phase II Reactions
Phase III Drugs Transporters
- further modification and excretion
• P-glycoprotein (P-gp)
• Multidrug resistanceassociated protein (MRP)
• Organic anion transporting polypeptide 2 (OATP2)
EX: Processing of glutathione conjugates to acetylcysteine conjugates.[
γ-glutamate and glycine residues in the glutathione molecule are removed by
Gamma-glutamyl transpeptidase and dipeptidases. In the final step, the
cystine residue in the conjugate is acetylated.
Conjugates and their metabolites can be excreted from cells in phase III of
their metabolism, with the anionic groups acting as affinity tags for a variety of
membrane transporters of the multidrug resistance protein (MRP) family
Receptors
• AhR (Aryl hydrocarbon receptor )
• Orphan nuclear receptors (DBD & LBD )
• Pregnane X receptor (PXR)
• Constitutive androstane receptor (CAR)
• Liver X receptor (LXR), TF, known as cholesterol sensors.
• Peroxisome proliferator activated receptors (PPAR): α,β,γ
• Farnesoid X receptor (FXR)
• Retinoid X Receptor (RXR): α,β,γ
REGULASI
CYP 1 by AhR
CYP2B CAR
CYP3A PXR
CYP4A PPAR
CYP7A LXR & FXR
A schematic representation of drugs/chemicals/xenobiotics-induced stress response leading to
the activation of specific receptor-mediated gene expression of phase I drug metabolizing
enzymes, the cytochrome p450s, phase II drug metabolizing enzymes, other stress enzymes,
And phase III transporters, which result in the enhancement of detoxification of the xenobiotics
and a potential homeostatic cell survival response.
The Phase Model of Xenobiotic Metabolism
• Metabolisme of lipophilic foreign compounds typically
proceeds in sequential steps.
• In Phase 1, the compounds are functionalized via introduction or

liberation of nucleophilic or electrophilic anchor groups by
oxidoreductases or hydrolases.
• These anchor groups allow phase 2 of XM conjugation of strongly

polar endogenous building blocks such as glucuronic acid and
gluthation, to the compounds.
• The resulting metabolites are usually readily water soluble and
can be excreted via bile or urine.
• The conjugation-rx often terminates the biological activity, such as

genotoxic effect of electrophiles or pharmacological efffects of
many therapeutic drugs.
The term "detoxification" is sometimes used for many of the reactions

involved in the metabolism of xenobiotics.
However, the term is not always appropriate because, as mentioned

above, in some cases the reactions to which xenobiotics are subject
actually increase their biologic activity and toxicity.
Cytochrome P450
• Isoforms of CYP450 hydroxylate a myriad of xenobiotics in
Phase 1 of their metabolism.
• Hydroxylation is the chief reaction involved in phase 1. The

responsible enzymes are called monooxygenases or CYP450.
• Approximately 60 CYP450 genes present in humans. The reaction

catalyzed by CYP450 is as follows:
RH above can represent a very wide variety of XB, including : drugs, carcinogens, pesticides,
petroleum products, and pollutants (such as a mixture of PCBs).
In addition, endogenous compounds, such as certain steroids, eicosanoids, fatty acids, and
retinoids, are also substrates. The substrates are generally lipophilic and are rendered more
hydrophilic by hydroxylation.
• CYP450 is considered the most versatile biocatalyst known.
• The actual rx mechanism is complex and has been briefly described

previously.
• It has been shown by the use of one atom of oxygen enters R–OH
and one atom enters water.
• This dual fate of the oxygen accounts for the former naming of
monooxygenases as "mixed-function oxidases." The reaction
catalyzed by CYP450 can also be represented as follows:
• Among reasons that this enzyme is important is the fact that
approximately 90% of the common drugs humans ingest are
metabolized by isoforms of CYP450.
• These enzymes also act on various carcinogens and pollutants.
• CYP450 are essential for the production of cholesterol, steroids,

prostacyclins, and thromboxane.
• The major CYP450s in drug metabolism are members of the CYP1,

CYP2, and CYP3 families: - CYP1A2,
- CYP2C9, CYP2C19, CYP2D6,
- CYP3A4, and CYP3A5
• CYP3A is the most important CYP450 involved in drug metabolism,

because of its abundance in liver and intestine.
The following are important points concerning CYP450
1. Systematic nomenclature for isoforms of P450 and for their genes.

CYP1A1 denotes a CYP450 that is a member of family 1 and
subfamily A and is the first individual member of that subfamily.
The gene encoding CYP1A1 is CYP1A1.
2. Like hemoglobin, they are hemoproteins.
3. They are widely distributed across species, including bacteria.
4. Present in highest amount in liver cells and enterocytes,

mainly in the membranes of the SRE,
5. At least 6 isoforms of CYP450 are present in the RE of human liver

6. NADPH, not NADH, is involved in the rx mechanism of CYP450
7. Lipids (PTCH) are also components of the CYP450 system
8. Most isoforms of CYP450 are inducible:

*CYP2C9 – Fenobrbital;
*CYP2E1 – Etanol
9. Certain isoforms of CYP450 (eg, CYP1A1) are particularly

involved in the metabolism of polycyclic aromatic hydrocarbons
(PAHs) and related molecules.
10. Certain CYP450s exist in polymorphic forms,ex:

* CYP2D6 - antihypertensive, antiarrhythmic and oxytocic drug.
* CYP2A6 - metabolism of nicotine to conitine
Responses to Xenobiotics Include
Pharmacologic, Toxic,
Immunologic, & Carcinogenic Effects

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Metabolism of Xenobiotics

• Understanding how xenobiotics are handled at the cellular level is

• For example, to modify microorganisms by introducing genes that

• These modified organisms will then be used to help dispose of

• Knowledge of the metabolism of xenobiotics is basic to a rational

• Hydroxylation may terminate the action of a drug, though this is

• In addition to hydroxylation, these enzymes catalyze a wide range

• Reactions involving hydrolysis (eg, by esterases) and certain

• The hydroxylated or other compounds produced in phase 1 are

• The overall purpose of the two phases of metabolism of

• In other cases, additional phase 1 reactions (eg, further hydroxylation

• In yet other cases, it is the conjugation reactions themselves that

• In a very few cases, conjugation may actually increase the biologic

• In Phase 1, the compounds are functionalized via introduction or

• These anchor groups allow phase 2 of XM conjugation of strongly

• The conjugation-rx often terminates the biological activity, such as

The term "detoxification" is sometimes used for many of the reactions

However, the term is not always appropriate because, as mentioned

• Hydroxylation is the chief reaction involved in phase 1. The

• Approximately 60 CYP450 genes present in humans. The reaction

• The actual rx mechanism is complex and has been briefly described

• These enzymes also act on various carcinogens and pollutants.

• CYP450 are essential for the production of cholesterol, steroids,

• The major CYP450s in drug metabolism are members of the CYP1,

• CYP3A is the most important CYP450 involved in drug metabolism,

1. Systematic nomenclature for isoforms of P450 and for their genes.

2. Like hemoglobin, they are hemoproteins.

3. They are widely distributed across species, including bacteria.

4. Present in highest amount in liver cells and enterocytes,

5. At least 6 isoforms of CYP450 are present in the RE of human liver

7. Lipids (PTCH) are also components of the CYP450 system

8. Most isoforms of CYP450 are inducible:

9. Certain isoforms of CYP450 (eg, CYP1A1) are particularly

10. Certain CYP450s exist in polymorphic forms,ex:

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