Basic Research for Individualized Medicine

细胞色素P450 2A 6（CYP 2A 6）参与替加氟、法倔唑和来曲唑等多种抗癌药物的代谢。值得注意的是，CYP 2A 6的表达水平及其在人体中的催化活性显示出广泛的个体间差异。这种变异的原因之一被认为是CYP 2A 6的遗传多态性。然而，这种变化不能完全解释报告的多态性。因此，我们调查了49名日本人和28名高加索人的CYP 2A 6基因。我们从这些样本中发现了45种新的遗传多态性。我们阐明，CYP 2A 6 ^*9（其在CYP 2A 6基因的5 '侧翼区域中含有SNP）降低了mRNA和蛋白质的表达，导致CYP 2A 6的酶活性降低。我们利用E.大肠杆菌表达系统和人肝微粒体中表达。CYP2A6.15（Lys 194 Glu）和CYP2A6.16（Arg 203 Ser）的香豆素7-羟化酶活性低于野生型CYP 2A 6。携带CYP 2A 6 ^*15或CYP 2A 6 ^*16等位基因的肝微粒体香豆素7-羟化酶活性低于携带CYP 2A 6 ^*1等位基因的肝微粒体香豆素7-羟化酶活性。这些变异等位基因被认为是CYP 2A 6活性个体间变异的原因之一。

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.