The CYP2C19 Intron 2 Branch Point SNP is the Ancestral Polymorphism Contributing to the Poor Metabolizer Phenotype in Livers with CYP2C19*35 and CYP2C19*2 Alleles

Chaudhry, Amarjit S.; Prasad, Bhagwat; Shirasaka, Yoshiyuki; Fohner, Alison E.; Finkelstein, David; Fan, Yiping; Wang, Shuoguo; Wu, Gang; Aklillu, Eleni; Sim, Sarah C.; Thummel, Kenneth E.; Schuetz, Erin G.

doi:10.1124/dmd.115.064428

Cited by 27 publications

(25 citation statements)

References 38 publications

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“…We note that SNP1, which is a mutation in the 3'-untranslated gene region, was significantly associated with reduced activities of CYP1A2, suggesting that this SNP play a role in CYP activities despite being in a non-coding region of the gene. Consistent with our study, studies focusing on common intronic and silent polymorphisms in the CYP2D6 and CYP2C19 genes [40,41] both indicated that intronic CYP SNPs were significantly associated with CYP activity. Studies on possible mechanisms are currently in progress.…”

Section: Discussionsupporting

confidence: 76%

Effect of P450 Oxidoreductase Polymorphisms on the Metabolic Activities of Ten Cytochrome P450s Varied by Polymorphic CYP Genotypes in Human Liver Microsomes

Fang¹,

Gao²,

Tian³

et al. 2018

Cell Physiol Biochem

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Background/ Aims: Little is known about the effect of P450 oxidoreductase (POR) gene polymorphisms on the activities of CYPs with multiple genotypes. Methods: We genotyped 102 human livers for 18 known POR single nucleotide polymorphisms (SNPs) with allelic frequencies greater than 1% as well as for 27 known SNPs in 10 CYPs. CYP enzyme activities in microsomes prepared from these livers were determined by measuring probe substrate metabolism by high performance liquid chromatograph. Results: We found that the effects of the 18 POR SNPs on 10 CYP activities were CYP genotype-dependent. The POR mutations were significantly associated with decreased overall K_m for CYP2B6 and 2E1, and specific genotypes within CYP1A2, 2A6, 2B6, 2C8, 2D6 and 2E1 were identified as being affected by these POR SNPs. Notably, the effect of a specific POR mutation on the activity of a CYP genotype could not be predicted from other CYP genotypes of even the same CYP. When combining one POR SNP with other POR SNPs, a hitherto unrecognized effect of multiple-site POR gene polymorphisms (MSGP) on CYP activity was uncovered, which was not necessarily consistent with the effect of either single POR SNP. Conclusions: The effects of POR SNPs on CYP activities were not only CYP-dependent, but more importantly, CYP genotype-dependent. Moreover, the effect of a POR SNP alone and in combination with other POR SNPs (MSGP) was not always consistent, nor predictable. Understanding the impact of POR gene polymorphisms on drug metabolism necessitates knowing the complete SNP complement of POR and the genotype of the relevant CYPs.

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Section: Discussionsupporting

confidence: 76%

Effect of P450 Oxidoreductase Polymorphisms on the Metabolic Activities of Ten Cytochrome P450s Varied by Polymorphic CYP Genotypes in Human Liver Microsomes

Fang¹,

Gao²,

Tian³

et al. 2018

Cell Physiol Biochem

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“…CYP2C19*35 encodes for a non-functional, truncated protein because nucleic acid substitution from adenine to guanine at position 12662 results in a premature stop codon due to the altered mRNA reading frame [35]. This variant allele was described by Chaudhry et al in 2015 [35] and has only been found in Blacks with African ancestry to date. In the present study, the finding of CYP2C19*35 in the Bateq sub-tribe may be attributed to their African heritage but the allele was not detected in Kensiu and Lanoh even though they are sub-tribes of Negrito.…”

Section: Discussionmentioning

confidence: 99%

Detection of CYP2C19 Genetic Variants in Malaysian Orang Asli from Massively Parallel Sequencing Data

Ang

Subramaniam

et al. 2016

PLoS ONE

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The human cytochrome P450 (CYP) is a superfamily of enzymes that have been a focus in research for decades due to their prominent role in drug metabolism. CYP2C is one of the major subfamilies which metabolize more than 10% of all clinically used drugs. In the context of CYP2C19, several key genetic variations that alter the enzyme’s activity have been identified and catalogued in the CYP allele nomenclature database. In this study, we investigated the presence of well-established variants as well as novel polymorphisms in the CYP2C19 gene of 62 Orang Asli from the Peninsular Malaysia. A total of 449 genetic variants were detected including 70 novel polymorphisms; 417 SNPs were located in introns, 23 in upstream, 7 in exons, and 2 in downstream regions. Five alleles and seven genotypes were inferred based on the polymorphisms that were found. Null alleles that were observed include CYP2C19*3 (6.5%), *2 (5.7%) and *35 (2.4%) whereas allele with increased function *17 was detected at a frequency of 4.8%. The normal metabolizer genotype was the most predominant (66.1%), followed by intermediate metabolizer (19.4%), rapid metabolizer (9.7%) and poor metabolizer (4.8%) genotypes. Findings from this study provide further insights into the CYP2C19 genetic profile of the Orang Asli as previously unreported variant alleles were detected through the use of massively parallel sequencing technology platform. The systematic and comprehensive analysis of CYP2C19 will allow uncharacterized variants that are present in the Orang Asli to be included in the genotyping panel in the future.

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“…This CYP2C19 alternative mRNA was perfectly correlated with an intron 2 SNP, rs12769205 (Chaudhry et al, 2015). A survey of multiple genomic databases indicated that rs12769205 and rs4244285 are in linkage disequilibrium with CYP2C19*2 (Fig.…”

Section: Introductionmentioning

confidence: 99%

Interindividual Variability in Cytochrome P450–Mediated Drug Metabolism

Tracy¹,

Chaudhry²,

Prasad³

et al. 2016

Drug Metabolism and Disposition

151

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The cytochrome P450 (P450) enzymes are the predominant enzyme system involved in human drug metabolism. Alterations in the expression and/or activity of these enzymes result in changes in pharmacokinetics (and consequently the pharmacodynamics) of drugs that are metabolized by this set of enzymes. Apart from changes in activity as a result of drug-drug interactions (by P450 induction or inhibition), the P450 enzymes can exhibit substantial interindividual variation in basal expression and/or activity, leading to differences in the rates of drug elimination and response. This interindividual variation can result from a myriad of factors, including genetic variation in the promoter or coding regions, variation in transcriptional regulators, alterations in microRNA that affect P450 expression, and ontogenic changes due to exposure to xenobiotics during the developmental and early postnatal periods. Other than administering a probe drug or cocktail of drugs to obtain the phenotype or conducting a genetic analysis to determine genotype, methods to determine interindividual variation are limited. Phenotyping via a probe drug requires exposure to a xenobiotic, and genotyping is not always well correlated with phenotype, making both methodologies less than ideal. This article describes recent work evaluating the effect of some of these factors on interindividual variation in human P450-mediated metabolism and the potential utility of endogenous probe compounds to assess rates of drug metabolism among individuals.

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The CYP2C19 Intron 2 Branch Point SNP is the Ancestral Polymorphism Contributing to the Poor Metabolizer Phenotype in Livers with CYP2C1935 and CYP2C192 Alleles

Cited by 27 publications

References 38 publications

Effect of P450 Oxidoreductase Polymorphisms on the Metabolic Activities of Ten Cytochrome P450s Varied by Polymorphic CYP Genotypes in Human Liver Microsomes

Effect of P450 Oxidoreductase Polymorphisms on the Metabolic Activities of Ten Cytochrome P450s Varied by Polymorphic CYP Genotypes in Human Liver Microsomes

Detection of CYP2C19 Genetic Variants in Malaysian Orang Asli from Massively Parallel Sequencing Data

Interindividual Variability in Cytochrome P450–Mediated Drug Metabolism

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