Effects of polymorphism in Promoter Region of Human CYP2A6 Gene (CYP2A6*9) on Expression Level of Messenger Ribonucleic Acid and Enzymatic Activity In Vivo and In Vitro
2003
Cytochrome P450 (CYP) 2A6 catalyzes nicotine C-oxidation, leading to cotinine formation, a major metabolic pathway of nicotine in humans. There are genetic polymorphisms in the human CYP2A6 gene. Previously, we demonstrated that in vivo nicotine metabolism is impaired with the CYP2A6*4, CYP2A6*7, and CYP2A6*10 alleles in Japanese subjects and Korean subjects. An allele possessing a point mutation in the TATA box termed CYP2A6*9 (T−48G) has been reported to decrease the transcriptional activity in vitro as assessed by luciferase assay. In this study we investigated the effects of the CYP2A6*9 allele on in vivo enzymatic activity by evaluating nicotine metabolism. The mutation of T−48G was found only on the CYP2A6*1A allele but not on the CYP2A6*1B allele. Allele frequencies of CYP2A6*9 in Japanese subjects (n = 92) and Korean subjects (n = 209) were 21.3% and 22.3%, respectively. In Korean subjects the cotinine/nicotine ratios as an index of nicotine metabolism in the subjects with CYP2A6*9/CYP2A6*9 (4.3 ± 2.4) were significantly lower than those in the subjects with CYP2A6*1A/CYP2A6*9 (7.7 ± 5.6) and CYP2A6*1A/CYP2A6*1A (10.4 ± 9.2) (P < .05 and P < .005, respectively). In Japanese subjects a similar result was observed, although it was not significant. Thus it is suggested that the mutation in the TATA box (CYP2A6*9 allele) caused the decreased in vivo enzymatic activity. With an in vitro study, it was shown that the expression levels of CYP2A6 messenger ribonucleic acid and coumarin 7-hydroxylase activity in human livers genotyped as CYP2A6*1/CYP2A6*9 and CYP2A6*9/CYP2A6*9 tended to be lower than those in human livers genotyped as CYP2A6*1/CYP2A6*1, although there was no significant difference because of the small number of samples. These in vitro data supported the in vivo data demonstrating that the CYP2A6*9 allele caused the decreased expression level and enzymatic activity of CYP2A6.
Clinical Pharmacology & Therapeutics (2003) 74, 69–76; doi: 10.1016/S0009-9236(03)00090-0
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