Distribution of polymorphic variants of CYP2A6 and their involvement in nicotine addiction

López-Flores, Luis Alberto; Pérez-Rubio, Gloría; Falfán-Valencia, Ramcés

doi:10.17179/excli2016-847

Cited by 9 publications

(6 citation statements)

References 144 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…CYP2A6 is involved in the metabolism of a large number of xenobiotic and is responsible for approximately 3% of the drugs metabolized by CYP enzymes. CYP2A6*4 , *7 , *10 , *11 , *19 , and *35 are highly distributed over East Asians, while CYP2A6*14 , *28 , and *34 have higher frequencies in Caucasian populations [ 28 ]. In our data, 3–12% of the population carried decreased-function alleles ( CYP2A6*4 , *7 , *9 , and *10 ) where their homozygous and heterozygous diplotypes were predicted as the slow metabolizer.…”

Section: Discussionmentioning

confidence: 99%

Genotypic and phenotypic landscapes of 51 pharmacogenes derived from whole-genome sequencing in a Thai population

Wankaew

Chariyavilaskul²,

Chamnanphon³

et al. 2022

PLoS ONE

View full text Add to dashboard Cite

Differences in drug responses in individuals are partly due to genetic variations in pharmacogenes, which differ among populations. Here, genome sequencing of 171 unrelated Thai individuals from all regions of Thailand was used to call star alleles of 51 pharmacogenes by Stargazer, determine allele and genotype frequencies, predict phenotype and compare high-impact variant frequencies between Thai and other populations. Three control genes, EGFR, VDR, and RYR1, were used, giving consistent results. Every individual had at least three genes with variant or altered phenotype. Forty of the 51 pharmacogenes had at least one individual with variant or altered phenotype. Moreover, thirteen genes had at least 25% of individuals with variant or altered phenotype including SLCO1B3 (97.08%), CYP3A5 (88.3%), CYP2C19 (60.82%), CYP2A6 (60.2%), SULT1A1 (56.14%), G6PD (54.39%), CYP4B1 (50.00%), CYP2D6 (48.65%), CYP2F1 (46.41%), NAT2 (40.35%), SLCO2B1 (28.95%), UGT1A1 (28.07%), and SLCO1B1 (26.79%). Allele frequencies of high impact variants from our samples were most similar to East Asian. Remarkably, we identified twenty predicted high impact variants which have not previously been reported. Our results provide information that contributes to the implementation of pharmacogenetic testing in Thailand and other Southeast Asian countries, bringing a step closer to personalized medicine.

show abstract

Section: Discussionmentioning

confidence: 99%

Genotypic and phenotypic landscapes of 51 pharmacogenes derived from whole-genome sequencing in a Thai population

Wankaew

Chariyavilaskul²,

Chamnanphon³

et al. 2022

PLoS ONE

View full text Add to dashboard Cite

show abstract

“…While high-prevalence alleles are observed for CYP2E1, their functional role has not been clearly established ( Hu et al, 1997 ; Zhou et al, 2017 ). The nonfunctional CYP2A6*4 and CYP2A6*7 alleles were not analyzed in this group since all liver donors were from Caucasian subjects, who have a low MAF (< 0.03) for these alleles ( López-Flores et al, 2017 ). Genomic DNA from the 113 liver specimens was genotyped using TaqMan probes following manufacturer’s suggested protocols.…”

Section: Methodsmentioning

confidence: 99%

CYP2C19 Plays a Major Role in the HepaticN-Oxidation of Cotinine

et al. 2022

View full text Add to dashboard Cite

The primary mode of metabolism of nicotine is via the formation of cotinine by the enzyme CYP2A6. Cotinine undergoes further CYP2A6-mediated metabolism by hydroxylation to 3-hydroxycotinine and norcotinine, but can also form cotinine- N -glucuronide and cotinine- N -oxide (COX). The goal of this study was to investigate the enzymes that catalyze COX formation and determine whether genetic variation in these enzymes may affect this pathway. Specific inhibitors of major hepatic cytochrome P450 (P450) enzymes were used in cotinine- N -oxidation reactions using pooled human liver microsomes (HLMs). COX formation was monitored by ultrahigh-pressure liquid chromatography–tandem mass spectrometry and enzyme kinetic analysis was performed using microsomes from P450-overexpressing human embryonic kidney 293 (HEK293) cell lines. Genotype-phenotype analysis was performed in a panel of 113 human liver specimens. Inhibition of COX formation was only observed in HLMs when using inhibitors of CYP2A6, CYP2B6, CYP2C19, CYP2E1, and CYP3A4. Microsomes from cells overexpressing CYP2A6 or CYP2C19 exhibited similar N -oxidation activity against cotinine, with maximum reaction rate over Michaelis constant values (intrinsic clearance) of 4.4 and 4.2 nL/min/mg, respectively. CYP2B6-, CYP2E1-, and CYP3A4-overexpressing microsomes were also active in COX formation. Significant associations ( P < 0.05) were observed between COX formation and genetic variants in CYP2C19 (*2 and *17 alleles) in HLMs. These results demonstrate that genetic variants in CYP2C19 are associated with decreased COX formation, potentially affecting the relative levels of cotinine in the plasma or urine of smokers and ultimately affecting recommended smoking cessation therapies. SIGNIFICANCE STATEMENT This study is the first to elucidate the enzymes responsible for cotinine- N -oxide formation and genetic variants that affect this biological pathway. Genetic variants in CYP2C19 have the potential to modify nicotine metabolic ratio in smokers and could affect pharmacotherapeutic decisions for smoking cessation treatments.

show abstract

“…To accurately capture the Cp-time profiles for MTD and its main metabolite hydroxy-MTD in this study, the ISEF value for CYP2A6 had to be increased to 13. As CYP2A6 is known to be a polymorphic enzyme [ 39 , 40 ], and the genotype information for the subjects involved in the studies was not reported, having a study-specific Vmax was anticipated. Both ISEF values were used to predict the MTD PK in the pregnant women.…”

Section: Resultsmentioning

confidence: 99%

PBPK Modeling Approach to Predict the Behavior of Drugs Cleared by Metabolism in Pregnant Subjects and Fetuses

Le Merdy,

Szeto,

Perrier

et al. 2024

Pharmaceutics

View full text Add to dashboard Cite

This study aimed to develop a physiologically based pharmacokinetic (PBPK) model that simulates metabolically cleared compounds’ pharmacokinetics (PK) in pregnant subjects and fetuses. This model accounts for the differences in tissue sizes, blood flow rates, enzyme expression levels, plasma protein binding, and other physiological factors affecting the drugs’ PK in both the pregnant woman and the fetus. The PBPKPlus™ module in GastroPlus® was used to model the PK of metoprolol, midazolam, and metronidazole for both non-pregnant and pregnant groups. For each of the three compounds, the model was first developed and validated against PK data in healthy non-pregnant volunteers and then applied to predict the PK in the pregnant groups. The model accurately described the PK in both the non-pregnant and pregnant groups and explained well the differences in the plasma concentration due to pregnancy. When available, the fetal plasma concentration, placenta, and fetal tissue concentrations were also predicted reasonably well at different stages of pregnancy. The work described the use of a PBPK approach for drug development and demonstrates the ability to predict differences in PK in pregnant subjects and fetal exposure for metabolically cleared compounds.

show abstract

Distribution of polymorphic variants of CYP2A6 and their involvement in nicotine addiction

Cited by 9 publications

References 144 publications

Genotypic and phenotypic landscapes of 51 pharmacogenes derived from whole-genome sequencing in a Thai population

Genotypic and phenotypic landscapes of 51 pharmacogenes derived from whole-genome sequencing in a Thai population

CYP2C19 Plays a Major Role in the HepaticN-Oxidation of Cotinine

PBPK Modeling Approach to Predict the Behavior of Drugs Cleared by Metabolism in Pregnant Subjects and Fetuses

Contact Info

Product

Resources

About