Functional Characterization of Novel Allelic Variants of CYP2C9 Recently Discovered in Southeast Asians

DeLozier, Tracy C.; Lee, Soo‐Chin; Coulter, Sherry J.; Goh, Boon Cher; Goldstein, Joyce A.

doi:10.1124/jpet.105.091181

Cited by 77 publications

(69 citation statements)

References 32 publications

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“…Thus, the reason for the CYP2C9*13-mediated reduction in drug-metabolizing capability is unclear. CYP2C9*14, CYP2C9*16, and CYP2C9*19 were found in Southeast Asians and reported to exhibit moderately or markedly decreased intrinsic clearance of tolbutamide in vitro (DeLozier et al, 2005). In our study, only CYP2C9*19 markedly decreased the intrinsic clearance of BOS (1.65%) and caused a lower V max value (2.1%) relative to wild type, consistent with previous observations.…”

Section: Discussionsupporting

confidence: 82%

Effects of Cytochrome P450 2C9 Polymorphism on Bosentan Metabolism

et al. 2014

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Cytochrome P450 (P450) 2C9 is an important member of the P450 enzyme superfamily, with 58 CYP2C9 allelic variants previously reported. Genetic polymorphisms of CYP2C9 significantly influence the efficacy and safety of some drugs, which might cause adverse effects and therapeutic failure. The aim of this study was to assess the catalytic activities of 38 human CYP2C9 alleles, including 24 novel alleles (*36-*60) found in the Han Chinese population, toward bosentan (BOS) in vitro. Insect microsomes expressing the 38 CYP2C9 alleles were incubated with 10-625 mM bosentan for 30 minutes at 37°C and terminated by cooling to 280°C immediately. BOS and hydroxyl bosentan, the major metabolite of BOS, were analyzed by ultraperformance liquid chromatography-tandem mass spectrometry system. Thirty-eight defective alleles can be classified into three categories according to the relative clearance value compared with wild type: nine alleles exhibited significantly increased intrinsic clearance values (V max /K m ) compared with the wild type (1.5-fold-∼4.9-fold relative clearance); nine alleles exhibited significantly reduced intrinsic clearance values compared with the wild type (0.6-28.9% relative clearance). The remaining 20 alleles exhibited no significant difference (1-fold) in enzyme activity compared with the wild type. These findings suggest that more attention should be directed to subjects carrying these infrequent CYP2C9 alleles when administering BOS in the clinic. This is the first report of all these rare alleles for BOS metabolism, providing fundamental data for further clinical studies on CYP2C9 alleles.

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Section: Discussionsupporting

confidence: 82%

Effects of Cytochrome P450 2C9 Polymorphism on Bosentan Metabolism

et al. 2014

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“…This allele was first identified in an Indian patient, and the variant protein exhibited 80-90% lower catalytic activity toward tolbutamide (7,8). CYP2C9*27 (Arg150Leu) and *30 (Ala477Thr), both detected recently in a Japanese population (11), were also identified in 3 and 2 individuals in the present study, respectively.…”

Section: Discussionsupporting

confidence: 71%

“…Arg133, the corresponding residue of CYP2B4, is suggested to play a prominent role in binding its redox partners, cytochrome b5 and P450 reductase (38). Accordingly, the loss of catalytic activity of the Arg132Gln variant might reflect the altered affinity of variant protein to these redox partners due to electrostatic changes as proposed for *2 (Arg144Cys), *14 (Arg125His), and *26 (Thr130Arg) (8,11,39).…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, interethnic variability reported in the pharmacokinetics and pharmacodynamics of drugs, metabolized mainly by CYP2C9, could not be fully explained by the common variants alone. Recently, a number of novel nonsynonymous variations of CYP2C9 have been identified in different Asian populations (6)(7)(8)(9)(10)(11). Functional analysis of these variations in vitro indicated the existence in Asians of new deleterious alleles of CYP2C9 that might have clinical relevance.…”

Section: Genetic Variations Of Cyp2c9 In 724 Japanese Individuals Andmentioning

confidence: 99%

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Genetic Variations of CYP2C9 in 724 Japanese Individuals and Their Impact on the Antihypertensive Effects of Losartan

et al. 2008

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“…CYP2C9*16(T299A) and CYP2C9*19(Q454H) were discovered after studying 125 Asians from Singapore (Zhao et al, 2004). In vitro study showed that CYP2C9*16 exhibited 80-90% lower catalytic activity of tolbutamide, whereas CYP2C9*19 exhibited 30-40% lower catalytic activity of tolbutamide, when compared with wild-type CYP2C9*1, CYP2C9*27, and CYP2C9*29 discovered in 263 Japanese individuals (DeLozier et al, 2005). Michaelis-Menten curves for diclofenac 4-hydroxylation from recombinant microsomes showed the identical Km and Vmax values of CYP2C9*27and CYP2C9*29 compared with the wild-type (Maekawa et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

In Vitro and In Vivo Characterization of 13 CYP2C9 Allelic Variants Found in Chinese Han Population

Pan

Wang

et al. 2015

Drug Metab Dispos

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Our previous study detected totally 35 CYP2C9 allelic variants in 2127 Chinese subjects, of whom 21 novel alleles were reported for the first time in Chinese populations. The aim of the present study was to characterize the 13 CYP2C9 allelic variants both in vitro and in vivo. Different types of CYP2C9 variants were highly expressed in COS-7 cells, and 50 mM tolbutamide was added as the probing substrate to evaluate their metabolic abilities in vitro. Subsequently, the concentrations of tolbutamide and its metabolite in the plasma and urine within individuals with different types of genotypes were determined by HPLC to evaluate the catalytic activity of the 13 mutant CYP2C9 proteins in vivo. Our results showed that compared with *1/*1 wild-type subjects, subjects with *1/*40 genotype showed increased oral clearance (CL/F), whereas individuals with

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Functional Characterization of Novel Allelic Variants of CYP2C9 Recently Discovered in Southeast Asians

Abstract: CYP2C9 was recently resequenced in 150 Asian subjects from Singapore. Several new coding variants were reported, and these variants are now named

Cited by 77 publications

References 32 publications

Effects of Cytochrome P450 2C9 Polymorphism on Bosentan Metabolism

Effects of Cytochrome P450 2C9 Polymorphism on Bosentan Metabolism

Genetic Variations of CYP2C9 in 724 Japanese Individuals and Their Impact on the Antihypertensive Effects of Losartan

In Vitro and In Vivo Characterization of 13 CYP2C9 Allelic Variants Found in Chinese Han Population

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