Basic Research for Individualized Medicine

点击翻译按钮获取中文摘要

Cytochrome P450 2A6 (CYP2A6) is involved in the metabolism of several kinds of anti cancer drugs, including tegafur, fadrozole and letrozole. Notably, the expression levels of CYP2A6 and its catalytic activities in humans show wide inter-individual variation. One of the causes of this variation has been thought to be the genetic polymorphisms of the CYP2A6. However, this variation could not be fully explained by reported polymorphisms. Therefore, we investigated the CYP2A6 gene of 49 Japanese and 28 Caucasian samples. We identified 45 novel genetic polymorphisms from these samples. We clarified that CYP2A6^*9, which contains SNP in the 5'-flanking region of the CYP2A6 gene, reduced the expression of mRNA and protein, leading to reduction of the enzymatic activities of CYP2A6. We investigate the function of mutant CYP2A6 caused by newly identified SNP using E. coli expression system and human liver microsomes. Coumarin 7-hydroxylase activities of CYP2A6.15 (Lys194Glu) and CYP2A6.16 (Arg203Ser) were lower than that of wild-type CYP2A6. Coumarin 7-hydroxylase activities of liver microsomes with CYP2A6^*15 or CYP2A6^*16 alleles were lower than that with CYP2A6^*1 alleles. These variant alleles were thought to be one of the causes of inter-individual variation of CYP2A6 activity.