CYP2D亚家族参与大鼠体内利多卡因的3-羟基化反应以及与肝微粒体蛋白共价结合的活性代谢物的形成。

Participation of the CYP2D subfamily in lidocaine 3-hydroxylation and formation of a reactive metabolite covalently bound to liver microsomal protein in rats.

作者信息

Masubuchi Y, Umeda S, Igarashi S, Fujita S, Narimatsu S, Suzuki T

机构信息

Laboratory of Biopharmaceutics, Faculty of Pharmaceutical Sciences, Chiba University, Japan.

出版信息

Biochem Pharmacol. 1993 Nov 17;46(10):1867-9. doi: 10.1016/0006-2952(93)90596-o.

DOI:10.1016/0006-2952(93)90596-o

PMID:8250975

Abstract

Lidocaine metabolism was investigated in rat liver microsomes and in a reconstituted system containing P450BTL, a cytochrome (P450) isozyme belonging to the CYP2D subfamily (Suzuki et al., Drug Metab Dispos 20: 367-373, 1992). P450BTL biotransformed lidocaine into 3-hydroxylidocaine (3-OH-LID) but not monoethylglycinexylidide and 2-methylhydroxylidocaine, in the reconstituted system including NADPH-P450 reductase and dilauroylphosphatidylcholine. An antibody against P450BTL inhibited microsomal lidocaine 3-hydroxylase activity by 97%. Thus, P450BTL and/or its immunorelated P450 isozyme(s) belonging to the CYP2D subfamily appear to be involved in lidocaine 3-hydroxylation. Furthermore, the antibody also suppressed the amounts of a lidocaine metabolite(s) bound to microsomal protein. These results suggest that the CYP2D subfamily biotransformed lidocaine into 3-OH-LID via an epoxy intermediate, which binds to microsomal macromolecules.

摘要

在大鼠肝微粒体以及包含P450BTL（一种属于CYP2D亚家族的细胞色素P450同工酶）的重组系统中研究了利多卡因的代谢（铃木等人，《药物代谢与处置》20: 367 - 373, 1992）。在包含NADPH - P450还原酶和二月桂酰磷脂酰胆碱的重组系统中，P450BTL将利多卡因生物转化为3 - 羟基利多卡因（3 - OH - LID），但不生成单乙基甘氨酰二甲苯酰胺和2 - 甲基羟基利多卡因。一种针对P450BTL的抗体使微粒体利多卡因3 - 羟化酶活性降低了97%。因此，P450BTL和/或其属于CYP2D亚家族的免疫相关P450同工酶似乎参与了利多卡因的3 - 羟化反应。此外，该抗体还抑制了与微粒体蛋白结合的利多卡因代谢物的量。这些结果表明，CYP2D亚家族通过一种环氧中间体将利多卡因生物转化为3 - OH - LID，该中间体与微粒体大分子结合。