Participation of the CYP2D subfamily in lidocaine 3-hydroxylation and formation of a reactive metabolite covalently bound to liver microsomal protein in rats.
Participation of the CYP2D subfamily in lidocaine 3-hydroxylation and formation of a reactive metabolite covalently bound to liver microsomal protein in rats.
复制标题
CYP2D 亚家族参与利多卡因 3-羟基化以及与大鼠肝微粒体蛋白共价结合的反应性代谢物的形成。
DOI：
10.1016/0006-2952(93)90596-o
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发表时间：
1993
影响因子：
5.8
通讯作者：
T. Suzuki
中科院分区：
文献类型：
--
作者：
Y. Masubuchi;S. Umeda;S. Igarashi;S. Fujita;S. Narimatsu;T. Suzuki
在大鼠肝微粒体和含有P450 BTL（属于CYP 2D亚家族的细胞色素（P450）同工酶）的重建系统中研究利多卡因代谢（Suzukiet al.，Drug Metab Dispos20：367-373，1992）。在含有NADPH-P450还原酶和二月桂酰磷脂酰胆碱的重组系统中，P450 BTL将利多卡因生物转化为3-羟基利多卡因（3-OH-LID），但不转化为单乙基甘氨酰二甲基苯胺和2-甲基羟基利多卡因。针对P450 BTL的抗体抑制微粒体利多卡因3-羟化酶活性达97%。因此，属于CYP 2D亚家族的P450 BTL和/或其免疫相关P450同工酶似乎参与利多卡因3-羟基化。此外，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，CYP 2D亚家族通过与微粒体大分子结合的环氧中间体将利多卡因生物转化为3-OH-LID。
Lidocaine metabolism was investigated in rat liver microsomes and in a reconstituted system containing P450BTL, a cytochrome (P450) isozyme belonging to the CYP2D subfamily (Suzukiet al., Drug Metab Dispos20: 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.