Cyp2d6
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The use of khat (Catha edulis) while on medication may alter treatment outcome. In particular, the influence of khat on the metabolic activities of drug-metabolizing enzymes is not known. We performed a comparative 1-way crossover study... more
The use of khat (Catha edulis) while on medication may alter treatment outcome. In particular, the influence of khat on the metabolic activities of drug-metabolizing enzymes is not known. We performed a comparative 1-way crossover study to evaluate the effect of khat on cyto-chrome P450 (CYP)2D6 and CYP3A4 enzyme activity. After 1 week of khat abstinence, baseline CYP2D6 and CYP3A4 metabolic activities were determined in 40 Ethiopian male volunteers using 30 mg dextromethor-phan (DM) as a probe drug and then repeated after 1 week of daily use of 400 g fresh khat leaves. Urinary concentrations of cathinone and cathine were determined to monitor the subjects' compliance to the study protocol. Genotyping for CYP2D6*3 and CYP2D6*4 was done. Plasma DM, dextrorphan and 3-methoxymorphinan concentrations were quantified. CYP2D6 and CYP3A4 enzyme activities were assessed by comparing plasma log DM/dextrorphan and log DM/methoxymorphinan metabolic ratio (MR) respectively in the presence and absence of khat. Cytochrome 2D6 MR was significantly increased from baseline by concurrent khat use (paired t test, P = 0.003; geometric mean ratio, 1.38; 95% confidence interval [95% CI], 1.12–1.53). Moreover, the inhibition of CYP2D6 activity by khat was more pronounced in CYP2D6*1/*1 compared with CYP2D6*1/*4 genotypes (P = 0.01). A marginal inhibition of CYP3A4 activity in the presence of khat was observed (P = 0.24). The mean percentage increase of CYP2D6 and CYP3A4 MR from baseline by khat use was 46% (95% CI,20–72) and 31% (95% CI, 8–54), respectively. This is the first report linking khat use with significant inhibition of CYP2D6 metabolic activity in humans.
A high frequency (7–10%) of CYP2D6 ultrarapid metabolizers estimated from the genotype (gUMs) has been claimed to exist among Spaniards and Southern Europeans. However, methodological aspects such as the inclusion of individuals carrying... more
A high frequency (7–10%) of CYP2D6 ultrarapid metabolizers estimated from the genotype (gUMs) has been claimed to exist among Spaniards and Southern Europeans. However, methodological aspects such as the inclusion of individuals carrying non-active multiplied alleles as gUMs may have led to an overestimation. Thus, this study aimed to analyze the gUM frequency (considering only those carrying more than two active genes) in 805 Spanish healthy volunteers studied for CYP2D6*2, *3, *4, *5, *6, *10, *17, *35, *41, and multiplications. Second, all worldwide studies reporting gUM frequencies were reviewed in order to evaluate potential misclassifications. The gUM frequency in this Spanish population was 5.34%, but increased to 8.3% if all individuals with CYP2D6 multiplications were classified as gUMs without considering the activity of the multiplied alleles. Moreover, among all reviewed worldwide studies only 55.6% precisely determined whether the multiplied alleles were active. Present results suggest that the evaluation of CYP2D6 ultrarapid metabolism should be standarized, and that the frequency of gUMs should be reconsidered in Spaniards and globally.
CYP2C9, CYP2C19 and CYP2D6 metabolize around 40 % of drugs and their genes vary across populations. The Costa Rican population has a trihybrid ancestry and its key geographic location turns it into a suitable scenario to evaluate... more
CYP2C9, CYP2C19 and CYP2D6 metabolize around 40 % of drugs and their genes vary across populations. The Costa Rican population has a trihybrid ancestry and its key geographic location turns it into a suitable scenario to evaluate interethnic differences across populations. This study aims to describe the diversity of CYP2C9, CYP2C19 and CYP2D6 polymorphisms in Costa Rican populations in the context of their ancestry. A total of 448 healthy individuals were included in the study: Bribri (n= 47), Cabécar (n= 27), Maleku (n= 16), Guaymí (n= 30), Huetar (n= 48), Chorotega (n= 41), Admixed/Mestizos from the Central Valley/Guanacaste (n= 189), and Afro-Caribbeans (n= 50) from Limón. CYP2C9 (alleles *2, *3, *6) and CYP2C19 (*2, *3, *4, *5, *17) genotypes were determined by Real-Time PCR. African, European and Native American ancestry were inferred using 87 ancestry informative markers. The frequency of the decreased activity allele CYP2C9*2 is lower in the self-reported Amerindian groups compared to the admixed population, and the highest frequencies of CYP2C19*2 (null activity) and the CYP2C19*17 (increased activity) were found in the self-reported Afro- Caribbean population. Moreover, a frequency of 0.7 % CYP2C9 gPMs in the Admixed population and a variable frequency of CYP2C19 gUMs (0.0-32.6 %, more prevalent in Afro-Caribbeans) in Costa Rican populations, was found. Finally, the following alleles were positively correlated with genomic African ancestry and negatively correlated with genomic Native American ancestry: CYP2D6*5 (null activity), CYP2D6*17 (decreased activity), CYP2D6*29 (decreased activity) and CYP2C19*17 (increased activity). No correlation for CYP2C9 polymor- phisms and genomic ancestry was found. Further studies assessing the CYP2C9 and CYP2C19 sequence in these populations, preferentially by sequencing these genes, are warranted. Rev. Biol. Trop. 64 (3): 1067-1076. Epub 2016 September 01.
- by Biología Tropical and +2
- •
- Costa Rica, Afro-Caribbean, CYP2C19, Amerindians
Aim: To determine the interaction of over-the-counter (OTC) and illicit psychostimulants at the cytochrome P450 enzyme, CYP2D6. CYP2D6 is responsible for 20% of hepatic Phase I metabolism and is a site of drug drug interactions, leading... more
Aim: To determine the interaction of over-the-counter (OTC) and illicit psychostimulants at the cytochrome P450 enzyme, CYP2D6. CYP2D6 is responsible for 20% of hepatic Phase I metabolism and is a site of drug drug interactions, leading to increased drug toxicity.
Materials and Methods: We examined the effects the OTC drugs; 1) the prototype H2-antagonist cimetidine (CMT) and 2) the opioid agonist cough suppressant dextromethorphan (DEX); as well as two scheduled drugs, methamphetamine (MA) and 3,4 methylenedioxymethamphetamine (MDMA) for their ability to interfere with CYP2D6 activity. Assays with human CYP2D6 determined the inhibitory potential (IC50) of each drug. Kinetic analysis (Vmax and Km) was accomplished using rodent hepatic microsomes.
Results: Maximum inhibition of CYP2D6 activity following exposure to CMT+MDMA was significantly reduced 75-85% compared to quinidine (control) values. These data showed inhibitory effects in CYP2D6 activity in each compound tested. Alterations in CYP2D6 activity may result in complex drug-drug interactions leading to elevated plasma levels of drugs and increased risk for toxicity. Assays using rat CYP2D2 demonstrated Vmax elevations in the CMT group (493%) compared to control (naïve, no treatment) values (19.9±5.1 pmol/mg protein/min). The Km was increased 218% in CMT compared to controls (3.1±0.5 μM). Collectively, all MA challenged groups exhibited increases in total enzyme [Vmax; 280-490%] and affinity [Km; 165-220%] values compared to the control group. The increase in both Vmax and Km suggests that the low affinity/high capacity CYP2D2 isoform is upregulated.
Conclusion: Our findings suggest that in vivo, MA acts as a CYP2D2-inducer, which will lead to altered secondary drug metabolism, increasing the risk of drug-related toxicity. Coupled with the ability of CMT and DEX to interfere with MA metabolism, a complex drug-drug interaction is possible, leading to increased toxicity. Our findings substantiate the hypothesis that the combination of illicit and OTC drugs could result in complex drug-drug interactions increasing the risk for severe drug-related toxicity.
Materials and Methods: We examined the effects the OTC drugs; 1) the prototype H2-antagonist cimetidine (CMT) and 2) the opioid agonist cough suppressant dextromethorphan (DEX); as well as two scheduled drugs, methamphetamine (MA) and 3,4 methylenedioxymethamphetamine (MDMA) for their ability to interfere with CYP2D6 activity. Assays with human CYP2D6 determined the inhibitory potential (IC50) of each drug. Kinetic analysis (Vmax and Km) was accomplished using rodent hepatic microsomes.
Results: Maximum inhibition of CYP2D6 activity following exposure to CMT+MDMA was significantly reduced 75-85% compared to quinidine (control) values. These data showed inhibitory effects in CYP2D6 activity in each compound tested. Alterations in CYP2D6 activity may result in complex drug-drug interactions leading to elevated plasma levels of drugs and increased risk for toxicity. Assays using rat CYP2D2 demonstrated Vmax elevations in the CMT group (493%) compared to control (naïve, no treatment) values (19.9±5.1 pmol/mg protein/min). The Km was increased 218% in CMT compared to controls (3.1±0.5 μM). Collectively, all MA challenged groups exhibited increases in total enzyme [Vmax; 280-490%] and affinity [Km; 165-220%] values compared to the control group. The increase in both Vmax and Km suggests that the low affinity/high capacity CYP2D2 isoform is upregulated.
Conclusion: Our findings suggest that in vivo, MA acts as a CYP2D2-inducer, which will lead to altered secondary drug metabolism, increasing the risk of drug-related toxicity. Coupled with the ability of CMT and DEX to interfere with MA metabolism, a complex drug-drug interaction is possible, leading to increased toxicity. Our findings substantiate the hypothesis that the combination of illicit and OTC drugs could result in complex drug-drug interactions increasing the risk for severe drug-related toxicity.
El gen CYP2D6 codifica para una monooxigenasa perteneciente al citocromo P450, la cual está involucrada en la biotransformación de un gran número de drogas comúnmente prescritas, como antidepresivos, antineoplásicos y antihipertensivos.... more
El gen CYP2D6 codifica para una monooxigenasa perteneciente al citocromo P450, la
cual está involucrada en la biotransformación de un gran número de drogas comúnmente
prescritas, como antidepresivos, antineoplásicos y antihipertensivos. Algunos
efectos adversos, así como falla terapéutica pueden ser relacionados con la actividad
anormal de CYP2D6 producto de polimorfismos en el gen de dicha enzima. Con el fin
de predecir la frecuencia de algunos fenotipos metabolizadores pobres de CYP2D6 en
la población de la región centroccidental de Venezuela se determinaron las frecuencias
alélicas y genotípicas de las variantes alélicas CYP2D6*3, *4 y *6. Se extrajo ADN genó-
mico a partir de sangre periférica de 100 individuos voluntarios aparentemente sanos, y
se procedió a la genotipificación por PCR tetra-primer alelo-específica y análisis por
electroforesis en geles de agarosa. Se compararon las frecuencias obtenidas con poblaciones
de otros países. El alelo más frecuente fue CYP2D6*4 con 16,5%, mostrando una
diferencia significativa con la reportada con poblaciones asiáticas. Este trabajo constituye
un estudio preliminar en la caracterización de un grupo más amplio de alelos de
CYP2D6 con el fin de asistir al desarrollo de una farmacoterapia individualizada en
nuestro país.
cual está involucrada en la biotransformación de un gran número de drogas comúnmente
prescritas, como antidepresivos, antineoplásicos y antihipertensivos. Algunos
efectos adversos, así como falla terapéutica pueden ser relacionados con la actividad
anormal de CYP2D6 producto de polimorfismos en el gen de dicha enzima. Con el fin
de predecir la frecuencia de algunos fenotipos metabolizadores pobres de CYP2D6 en
la población de la región centroccidental de Venezuela se determinaron las frecuencias
alélicas y genotípicas de las variantes alélicas CYP2D6*3, *4 y *6. Se extrajo ADN genó-
mico a partir de sangre periférica de 100 individuos voluntarios aparentemente sanos, y
se procedió a la genotipificación por PCR tetra-primer alelo-específica y análisis por
electroforesis en geles de agarosa. Se compararon las frecuencias obtenidas con poblaciones
de otros países. El alelo más frecuente fue CYP2D6*4 con 16,5%, mostrando una
diferencia significativa con la reportada con poblaciones asiáticas. Este trabajo constituye
un estudio preliminar en la caracterización de un grupo más amplio de alelos de
CYP2D6 con el fin de asistir al desarrollo de una farmacoterapia individualizada en
nuestro país.
Objective Linkage disequilibrium (LD) and recombination rate variations are known to vary considerably between human genome regions and populations mostly because of the combined effects of mutation, recombination, and demographic... more
Objective Linkage disequilibrium (LD) and recombination
rate variations are known to vary considerably between
human genome regions and populations mostly because
of the combined effects of mutation, recombination, and
demographic history. Thus, the pattern of LD is a key issue
to disentangle variants associated with complex traits. Here,
we aim to describe the haplotype structure and LD variation
at the pharmacogenetically relevant cytochrome P450 CYP2C
and CYP2D gene regions among European populations.
Methods To assess the haplotype structure, LD pattern,
and recombination rate variations in the clinically
significant CYP2C and CYP2D regions, we genotyped 143
single-nucleotide polymorphisms (SNPs) across these two
genome regions in a diverse set of 11 European population
samples and one sub-Saharan African sample.
Results Our results showed extended patterns of LD and
in general a low rate of recombination at these loci, and a
low degree of allele differentiation for the two cytochrome
P450 regions among Europeans, with the exception of the
Sami and the Finns as European outliers. The Sami sample
showed reduced haplotype diversity and higher LD for the
two cytochrome P450 regions than the other Europeans,
a feature that is proposed to enhance the LD mapping of
underlying common complex traits. However,
recombination hotspots and LD blocks at these two regions
showed highly consistent structures across Europeans
including Finns and Sami. Moreover, we showed that the
CEPH sample has significantly higher tag transferability
among Europeans and a more efficient tagging of both the
rare CYP2C9 and the common CYP2C19 functional variants
than the Sami. Our data set included CYP2C9*3
(rs1057910) and CYP2C19*2 (rs4244285) enzyme activityaltering
variants associated in a recent genome-wide study
with acenocoumarol-induced and warfarin-induced
anticoagulation or to the antiplatelet effect of clopidogrel,
respectively. Including these known activity-altering
variants, we showed the haplotype variation and high
derived allele frequencies of novel recently identified
acenocoumarol genome-wide associated SNPs at CYP2C9(rs4086116) and CYP2C18 (rs12772169, rs1998591,
rs2104543, rs1042194) loci in a comprehensive set of 11
European populations. Furthermore, a significant frequency
difference of a CYP2C19*2 gene mutation causing variable
drug reactions was observed among Europeans.
Conclusion The CEPH sample representing the general
European population as such in the HapMap project seems
to be the optimal population sample for the LD mapping of
common complex traits among Europeans. Nevertheless, it
is still argued that the unique pattern of LD in the Sami may
offer an advantage for further association mapping,
especially if multiple rare variants play a role in disease
etiology. However, besides the activity-altering CYP2C9*3
(rs1057910) and CYP2C19*2 (rs4244285) variants, the
high derived allele frequencies of novel recently identified
acenocoumarol genome-wide associated SNPs at CYP2C9
(rs4086116) and CYP2C18 (rs12772169, rs1998591,
rs2104543, rs1042194) loci variants indicated that the
CYP2C region may have been influenced by selection. Thus,
this fine-scale haplotype map of the CYP2C and CYP2D
regions may help to choose markers for further association
mapping of complex pharmacogenetic traits at these
loci.
rate variations are known to vary considerably between
human genome regions and populations mostly because
of the combined effects of mutation, recombination, and
demographic history. Thus, the pattern of LD is a key issue
to disentangle variants associated with complex traits. Here,
we aim to describe the haplotype structure and LD variation
at the pharmacogenetically relevant cytochrome P450 CYP2C
and CYP2D gene regions among European populations.
Methods To assess the haplotype structure, LD pattern,
and recombination rate variations in the clinically
significant CYP2C and CYP2D regions, we genotyped 143
single-nucleotide polymorphisms (SNPs) across these two
genome regions in a diverse set of 11 European population
samples and one sub-Saharan African sample.
Results Our results showed extended patterns of LD and
in general a low rate of recombination at these loci, and a
low degree of allele differentiation for the two cytochrome
P450 regions among Europeans, with the exception of the
Sami and the Finns as European outliers. The Sami sample
showed reduced haplotype diversity and higher LD for the
two cytochrome P450 regions than the other Europeans,
a feature that is proposed to enhance the LD mapping of
underlying common complex traits. However,
recombination hotspots and LD blocks at these two regions
showed highly consistent structures across Europeans
including Finns and Sami. Moreover, we showed that the
CEPH sample has significantly higher tag transferability
among Europeans and a more efficient tagging of both the
rare CYP2C9 and the common CYP2C19 functional variants
than the Sami. Our data set included CYP2C9*3
(rs1057910) and CYP2C19*2 (rs4244285) enzyme activityaltering
variants associated in a recent genome-wide study
with acenocoumarol-induced and warfarin-induced
anticoagulation or to the antiplatelet effect of clopidogrel,
respectively. Including these known activity-altering
variants, we showed the haplotype variation and high
derived allele frequencies of novel recently identified
acenocoumarol genome-wide associated SNPs at CYP2C9(rs4086116) and CYP2C18 (rs12772169, rs1998591,
rs2104543, rs1042194) loci in a comprehensive set of 11
European populations. Furthermore, a significant frequency
difference of a CYP2C19*2 gene mutation causing variable
drug reactions was observed among Europeans.
Conclusion The CEPH sample representing the general
European population as such in the HapMap project seems
to be the optimal population sample for the LD mapping of
common complex traits among Europeans. Nevertheless, it
is still argued that the unique pattern of LD in the Sami may
offer an advantage for further association mapping,
especially if multiple rare variants play a role in disease
etiology. However, besides the activity-altering CYP2C9*3
(rs1057910) and CYP2C19*2 (rs4244285) variants, the
high derived allele frequencies of novel recently identified
acenocoumarol genome-wide associated SNPs at CYP2C9
(rs4086116) and CYP2C18 (rs12772169, rs1998591,
rs2104543, rs1042194) loci variants indicated that the
CYP2C region may have been influenced by selection. Thus,
this fine-scale haplotype map of the CYP2C and CYP2D
regions may help to choose markers for further association
mapping of complex pharmacogenetic traits at these
loci.
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