Effect of P450 oxidoreductase variants on the metabolism of model substrates mediated by CYP2C9.1, CYP2C9.2, and CYP2C9.3

Subramanian, Murali; Agrawal, Vishal; Sandee, Duanpen; Tam, Harrison K.; Miller, Walter L.; Tracy, Timothy S.

doi:10.1097/fpc.0b013e3283544062

Cited by 42 publications

(38 citation statements)

References 38 publications

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“…The fact that losartan pharmacokinetics is affected by the CYP2C9*3 polymorphism, but not by CYP2C9*2, could be explained because *3 allele codes for an enzyme with lower activity than the one by *2 allele. In this sense, subjects with *2 allele have an intermediate activity phenotype and *3 allele carriers showed a low activity phenotype (Subramanian et al, 2012). In addition, other studies have shown pharmacokinetic associations with CYP2C9*3 but not with CYP2C9*2 (Lee et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

Evaluation of the Relationship between Sex, Polymorphisms in CYP2C8 and CYP2C9, and Pharmacokinetics of Angiotensin Receptor Blockers

et al. 2012

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Angiotensin II receptor blockers (ARBs) are used to treat hypertension. Most ARBs are metabolized by CYP2C9. The aim of this study is to evaluate the possible association between sex, polymorphisms in the CYP2C8 and CYP2C9 genes, and the pharmacokinetics of losartan, valsartan, candesartan, and telmisartan. The study population comprised 246 healthy volunteers from seven single-dose clinical trials: 64 from two candesartan studies, 43 from a telmisartan study, 36 from a losartan study, and 103 from three valsartan studies. DNA was extracted from blood samples and single-nucleotide polymorphisms in the CYP2C8 (CYP2C8*2, CYP2C8*3, CYP2C8*4, CYP2C8*5) and CYP2C9 (CYP2C9*2, CYP2C9*3) genes were evaluated using real-time polymerase chain reaction. Sex only affected telmisartan pharmacokinetics, since women showed a higher telmisartan C max than men (590.5 6 75.8 ng/ml versus 282.1 6 30.8 ng/ml; P £ 0.01). CYP2C9 variants were associated only with losartan pharmacokinetics: the half-life of losartan was higher in CYP2C9*3 allele carriers (3.1 6 0.4 hours) than in volunteers with the wild-type genotype (2.3 6 0.1 hours) (P £ 0.05). CYP2C8 polymorphisms were associated only with valsartan pharmacokinetics, since *2 allele carriers showed faster clearance (1.07 6 0.57 l/h·kg) than those with the wild-type genotype (0.48 6 0.72 l/h·kg; P £ 0.01) and carriers of the *3 allele (0.35 6 0.49 l/h·kg; P £ 0.001). These results suggest that genotypes for CYP2C9 and CYP2C8 are relevant to the pharmacokinetics of losartan and valsartan, respectively, but not the pharmacokinetics of candesartan or telmisartan.

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Section: Discussionmentioning

confidence: 99%

Evaluation of the Relationship between Sex, Polymorphisms in CYP2C8 and CYP2C9, and Pharmacokinetics of Angiotensin Receptor Blockers

et al. 2012

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“…Four different cDNA expression systems have been successfully used for the in vitro drug metabolism studies, including bacteria [22], yeast [23], insect cells [24] and mammalian cells [13]. Compared with other expression systems, mammalian cells have adequate endogenous OR and cytochrome b 5 to support CYP activities and are much closer to the inherent environment of human proteins; thus, it is much more relevant to assess the potential effects of recombinant human CYP variant proteins in the mammalian cell system [21].…”

Section: Resultsmentioning

confidence: 99%

In Vitro Functional Assessment of 22 Newly Identified CYP2D6 Allelic Variants in the Chinese Population

Dai

Geng

Wang

et al. 2015

Basic Clin Pharma Tox

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Cytochrome P450 2D6 (CYP2D6) is one of the most widely investigated CYPs related to genetic polymorphisms and is responsible for one-quarter of the currently used clinical drugs. We previously detected 22 novel, non-synonymous, mutated sites in the Chinese population, but nothing is known about the functional effects of these mutations in terms of specific CYP2D6 substrates. In this study, wild-type CYP2D6, two common allelic variants and 22 newly reported CYP2D6 isoforms were transiently expressed in 293FT cells, and the enzymatic activities of these variants were systematically assessed using dextromethorphan and bufuralol as the probing substrates. Consequently, 19 and 21 allelic variants were found to exhibit significantly decreased enzymatic activities for dextromethorphan and bufuralol, respectively. Of 22 novel CYP2D6 variants, six allelic isoforms (CYP2D6.89, CYP2D6.92, CYP2D6.93, CYP2D6.96, E215K and R440C) exhibited absent or extremely reduced metabolic activities compared with those observed for the wild-type enzyme. Our in vitro functional data can be useful for CYP2D6 phenotype prediction and provide valuable information for the study of clinical impact of these newly found CYP2D6 variants in China.As one of the most important drug-metabolizing enzymes, cytochrome P450 2D6 (CYP2D6) is responsible for approximately 25% of clinically used drugs including analgesics, antiarrhythmics, antiemetics, antipsychotics, antidepressants, beta-adrenergic blockers and chemotherapeutic/hormone replacement agents [1][2][3]. Similar to other P450 subfamily members, the CYP2D6 gene locus is also highly polymorphic across different ethnic populations and individuals [4]. To date, a total of 105 allelic variants are defined and described in the Human CYP Allele Nomenclature database (http://www.cypalleles.ki.se/cyp2d6.htm). These genetic variants can be associated with increased, decreased or abolished enzymatic functions, which results in differences of up to 30-to 40-fold changes in substrate drug clearance values. Consequently, these differences in CYP2D6 activity have been demonstrated to be prominent contributors to interindividual drug response variability [2,5,6].It has been reported that significant ethnic and geographic differences exist in CYP2D6 alleles [7,8]. For Eastern Asians, only 1-2% of individuals have been found to be poor metabolizers (PMs), and approximately 57% of the Chinese population are intermediate metabolizers (IMs) [9,10]. Polymorphic studies have revealed that the IM allele CYP2D6*10 is predominant in Asian populations with frequencies ranging from 30% to 50% [7,11]. In a recent large-scale, genetic screening study, we sequenced all nine exons of the CYP2D6 gene in 2129 unrelated Chinese individuals. As a result, 22 new nonsynonymous, mutated sites were found, and 12 of them were designated as novel alleles (*87-*93, *94A, *94B and *95-*98) by the Human CYP Allele Nomenclature Committee [12]. Considering the fact that there are more than 1.4 billion people living in the mainland ...

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“…Only one study [10] has characterized the impact of a single common POR SNP, A503V, on the activity of the CYP3A5*1/*1 and CYP3A5*3/*3 genotypes in vivo. Two studies in reconstituted systems revealed different effects on CYP2C8 variants [21] and CYP2C9 variants [22]; however, these studies were performed with a very limited number of POR mutations and CYP isoforms. Human liver microsomes (HLMs) provide a valuable means to test the effect of POR polymorphisms on CYP activity because they contain the enzymes in their native environment.Unfortunately, no studies on the activities of different CYP genotypes have been conducted with HLMs.…”

Section: Introductionmentioning

confidence: 99%

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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Effect of P450 oxidoreductase variants on the metabolism of model substrates mediated by CYP2C9.1, CYP2C9.2, and CYP2C9.3

Abstract: POR variants affect CYP2C9 activities. The impact of a POR variant on catalysis varies with the isoform of CYP2C9 and the assay substrate.

Cited by 42 publications

References 38 publications

Evaluation of the Relationship between Sex, Polymorphisms in CYP2C8 and CYP2C9, and Pharmacokinetics of Angiotensin Receptor Blockers

Evaluation of the Relationship between Sex, Polymorphisms in CYP2C8 and CYP2C9, and Pharmacokinetics of Angiotensin Receptor Blockers

In Vitro Functional Assessment of 22 Newly Identified CYP2D6 Allelic Variants in the Chinese Population

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

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