CYP2C9 Ile359 and Leu359 variants: enzyme kinetic study with seven substrates

Takanashi, Koichi; Tainaka, Hitoshi; Kobayashi, Kaoru; Yasumori, Toshio; Hosakawa, Masakiyo; Chiba, Kazuhiro

doi:10.1097/00008571-200003000-00001

Cited by 247 publications

(153 citation statements)

References 29 publications

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“…14 The CYP2C9 singlenucleotide polymorphisms result in a reduced intrinsic drug clearance, 12,15 but the magnitude of the effect, which ranges from 3-to 34-fold, appears to be drug-dependent. 16 Previous rodent studies have established a role for cytochrome P450 enzymes in the hepatic biotransformation of VPA to form 4-ene-VPA (Figure 1), which is a hepatotoxic metabolite. 4 In a study with human liver microsomes and cDNA-expressed cytochrome P450 enzymes, it was concluded that CYP2C9 catalyzes the metabolic activation of VPA to form 4-ene-VPA.…”

Section: Introductionmentioning

confidence: 97%

Influence of CYP2C9 genotypes on the formation of a hepatotoxic metabolite of valproic acid in human liver microsomes

Abbott

Zanger

et al. 2003

Pharmacogenomics J

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The present study investigated the effect of cytochrome P450 2C9 (CYP2C9) genetic polymorphism on the biotransformation of valproic acid (VPA) to its hepatotoxic metabolite, 4-ene-VPA, and compared that to the formation of the inactive 4-OH-VPA and 5-OH-VPA. cDNA-expressed CYP2C9*2 and CYP2C9*3 variants were less efficient than the CYP2C9*1 wild type in catalyzing the formation of these metabolites, as assessed by the ratio of Vmax and apparent Km (in vitro intrinsic clearance). The reduced efficiency by CYP2C9*2 was due to a reduced Vmax, whereas, in the case of CYP2C9*3, it was the result of increased apparent Km. The formation rates of 4-ene-VPA, 4-OH-VPA, and 5-OH-VPA in human liver microsomes were reduced by 29, 28, and 31%, respectively, in samples with one mutated CYP2C9 allele, and by 61, 73, and 58%, respectively, in samples with two mutated CYP2C9 alleles. Overall, the homozygote and heterozygote CYP2C9*2 and CYP2C9*3 genotypes may compromise hepatic VPA biotransformation.

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Section: Introductionmentioning

confidence: 97%

Influence of CYP2C9 genotypes on the formation of a hepatotoxic metabolite of valproic acid in human liver microsomes

Abbott

Zanger

et al. 2003

Pharmacogenomics J

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“…Warfarin pharmacokinetics are affected by functional polymorphisms (*2, Arg144Cys; *3, Ile359Leu) in cytochrome P450 2C9 (CYP2C9). 5,6 In addition, warfarin's effects are modulated by polymorphisms (eg, Ϫ1639, rs9923231) in the vitamin K epoxide reductase complex 1 (VKORC1) enzyme, a critical component of the vitamin K cycle discovered in part because of its contribution to bleeding disorders and warfarin resistance. 7,8 Both VKORC1 and CYP2C9 polymorphisms independently correlate with warfarin dose 9,10 and other clinical outcomes such as time to stabilized dose, bleeding events, and time within the target therapeutic range.…”

Section: Introductionmentioning

confidence: 99%

A genome-wide scan for common genetic variants with a large influence on warfarin maintenance dose

Cooper

Johnson

Langaee³

et al. 2008

Blood

410

302

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Warfarin dosing is correlated with polymorphisms in vitamin K epoxide reductase complex 1 (VKORC1) and the cytochrome P450 2C9 (CYP2C9) genes. Recently, the FDA revised warfarin labeling to raise physician awareness about these genetic effects. Randomized clinical trials are underway to test genetically based dosing algorithms. It is thus important to determine whether common single nucleotide polymorphisms (SNPs) in other gene(s) have a large effect on warfarin dosing. A retrospective genome-wide association study was designed to identify polymorphisms that could explain a large fraction of the dose variance. White patients from an index warfarin population (n ‫؍‬ 181) and 2 independent replication patient populations (n ‫؍‬ 374) were studied. From the approximately 550 000 polymorphisms tested, the most significant independent effect was associated with VKORC1 polymorphisms (P ‫؍‬ 6.2 ؋ 10 ؊13 ) in the index patients. CYP2C9 (rs1057910 CYP2C9*3) and rs4917639) was associated with dose at moderate significance levels (P ϳ 10 ؊4 ). Replication polymorphisms (355 SNPs) from the index study did not show any significant effects in the replication patient sets. We conclude that common SNPs with large effects on warfarin dose are unlikely to be discovered outside of the CYP2C9 and VKORC1 genes. Randomized clinical trials that account for these 2 genes should therefore produce results that are definitive and broadly applicable. IntroductionThe determination of safe yet effective doses of warfarin for individual patients is one of the most promising clinical applications of pharmacogenetics. [1][2][3] There are large variation in warfarin dose from patient to patient and significant clinical consequences of doses that produce insufficient or excessive pharmacologic effects. Thus, reducing uncertainty in establishing the therapeutic dose in individual patients could improve quality of care as well as expand the range of patients who could be treated. 4 In white patients, genetic factors are more strongly correlated with stabilized warfarin dose than all other known patient-related factors. Warfarin pharmacokinetics are affected by functional polymorphisms (*2, Arg144Cys; *3, Ile359Leu) in cytochrome P450 2C9 (CYP2C9). 5,6 In addition, warfarin's effects are modulated by polymorphisms (eg, Ϫ1639, rs9923231) in the vitamin K epoxide reductase complex 1 (VKORC1) enzyme, a critical component of the vitamin K cycle discovered in part because of its contribution to bleeding disorders and warfarin resistance. 7,8 Both VKORC1 and CYP2C9 polymorphisms independently correlate with warfarin dose 9,10 and other clinical outcomes such as time to stabilized dose, bleeding events, and time within the target therapeutic range. [11][12][13] Combined polymorphisms in VKORC1 and CYP2C9 explain approximately 30% (20%-25% for VKORC1; 5%-10% for CYP2C9) of the variance in the stabilized warfarin dose distribution. 10,14,15 The importance of these strong genetic effects was recognized by recent relabeling of warfarin by the FDA to raise awar...

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“…The different alleles code for enzymes with different amino acid composition, and the functional significance of this polymorphism has been studied both in vitro and in vivo . For several CYP2C9 substrates, metabolism by the CYP2C9.3 enzyme variant is markedly reduced compared to the enzyme encoded by CYP2C9 * 1 [6,8,9] . This has clinical implications for CYP2C9 drugs with narrow therapeutic windows, such as warfarin and phenytoin, where drug accumulation due to slow metabolism will increase the risk of severe adverse reactions [10][11][12].…”

Section: Introductionmentioning

confidence: 99%

Oxidation of celecoxib by polymorphic cytochrome P450 2C9 and alcohol dehydrogenase

Sandberg

Yaşar

Strömberg

et al. 2002

Brit J Clinical Pharma

102

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Aims Celecoxib is a novel selective cyclooxygenase-2 inhibitor, which is subject to extensive hepatic metabolism. The aims of the present in vitro investigation were 1) to compare the rate of celecoxib hydroxylation by different genetic variants of cytochrome P450 2C9 (CYP2C9), and 2) to identify the enzyme(s) involved in the formation of the major metabolite carboxycelecoxib. Methods Hydroxycelecoxib formation was studied in human liver microsomes from 35 genotyped livers, as well as in yeast microsomes with recombinant expression of different P450 variants. Carboxycelecoxib formation was studied in liver microsomes incubated in the absence or presence of liver cytosol. The metabolites were identified and quantified by h.p.l.c. In addition, hydroxycelecoxib oxidation by different variants of recombinant human alcohol dehydrogenase (ADH1-3) was analysed by spectrophotometric monitoring of NADH generation from NAD + . Results The intrinsic clearance of celecoxib hydroxylation was significantly lower for yeast-expressed CYP2C9.3 (0.14 ml min − 1 nmol − 1 enzyme) compared with CYP2C9.1 (0.44 ml min − 1 nmol − 1 enzyme). In human liver microsomes, a significant 2-fold decrease in the rate of hydroxycelecoxib formation was evident in CYP2C9 * 1/ * 3 samples compared with CYP2C9 * 1/ * 1 samples. There was also a marked reduction (up to 5.3 times) of hydroxycelecoxib formation in a liver sample genotyped as CYP2C9 * 3/ * 3 . However, the CYP2C9 * 2 samples did not differ significantly from CYP2C9 * 1 in any of the systems studied. Inhibition experiments with sulphaphenazole (SPZ) or triacetyloleandomycin indicated that celecoxib hydroxylation in human liver microsomes was mainly dependent on CYP2C9 and not CYP3A4. The further oxidation of hydroxycelecoxib to carboxycelecoxib was completely dependent on liver cytosol and NAD + . Additional experiments showed that ADH1 and ADH2 catalysed this reaction in vitro with apparent K m values of 42 µ M and 10 µ M , respectively, whereas ADH3 showed no activity. Conclusions The results confirm that CYP2C9 is the major enzyme for celecoxib hydroxylation in vitro and further indicate that the CYP2C9 * 3 allelic variant is associated with markedly slower metabolism. Furthermore, it was shown for the first time that carboxycelecoxib formation is dependent on cytosolic alcohol dehydrogenase, presumably ADH1 and/or ADH2.

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CYP2C9 Ile359 and Leu359 variants: enzyme kinetic study with seven substrates

Cited by 247 publications

References 29 publications

Influence of CYP2C9 genotypes on the formation of a hepatotoxic metabolite of valproic acid in human liver microsomes

Influence of CYP2C9 genotypes on the formation of a hepatotoxic metabolite of valproic acid in human liver microsomes

A genome-wide scan for common genetic variants with a large influence on warfarin maintenance dose

Oxidation of celecoxib by polymorphic cytochrome P450 2C9 and alcohol dehydrogenase

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