CYP2D6ならびにCYP2E1遺伝子多型と肝ミクロゾーム薬物酸化活性との関係
ー日本人39例、欧米人45例における解析ー
2000 年 15 巻 supplement 号 p. 84-85
詳細
2000 年 15 巻 supplement 号 p. 84-85
Twenty one types of genetic polymorphisms in CYP2D6 gene were determined in liver DNA of Japanese and Caucasians and compared these CYP2D6 genotypes with CYP2D6 protein levels and bufuralol 1'- and 6-hydroxylation activities in liver microsomes of these human samples. We detected 11 types of CYP2D6 genetic polymorphisms and classified these humans into 17 genotypes; 7 types were found in the Japanese and 13 types in the Caucasian. CYP2D6* 10B, but not CYP2D6*10A, was the most frequent in mutation at 34.6% in the Japanese, whereas in Caucasians, CYP2D6 polymorphisms including CYP2D6*4A, *4D, *4E, *4L *3, *9, and *M12 (frequencies at 6.8, 3.4, 4.5, 9.1, 2.3, 2.3, 4.5%) respectively, were detected. A Caucasian having homozygous CYP2D6*3/*3 had a protein with slower gel mobility (immunoblotting with anti-CYP2D6 antibody) and a very low activity for bufuralol 1'-hydroxylation. Five Caucasian samples with CYP2D6*4A/*4A, *4A/*4L, or *4D/*4L had no measurable CYP2D6 protein and very low bufuralol 1'-hydroxylation activities. Seven Japanese subjects with CYP2D6*10B/*IOB had CYP2D6 protein at levels of -20% of those present in humans with CYP2D6*1 and *2 and catalyzed bufuralol 1'-hydroxylation at low rates. These results support the view that CYP2D6*3, *4A, *4D, and *4L are major genotypes in producing poor metabolizer phenotypes in CYP2D6 in Caucasians, whereas CYP2D6*10B is a major causes in decreasing CYP2D6 protein expression and catalytic activities in Japanese. We also determine three types of CYP2E1 genetic polymorphisms, namely RsaI/PstI-, DraI-, and MspI-types, and compared these genotypes with levels of CYP2E1 and activities of 7-ethoxycoumarin O-deethylation and chlorzoxazone 6-hydroxylation in liver microsomes from these human samples. The results obtained collectively indicated that RsaI/PstI-, DraI-, and MspI-types of CYP2E1 polymorphisms may not cause significant alterations in protein expression and enzyme catalytic activities of CYP2E1 enzyme in human livers.
