蒂巴因O-去甲基化生成阿片碱：两种大鼠品系之间的遗传差异。

Thebaine O-demethylation to oripavine: genetic differences between two rat strains.

Mikus G, Somogyi A A, Bochner F, Eichelbaum M

Department of Clinical and Experimental Pharmacology, University of Adelaide, Australia.

Xenobiotica. 1991 Nov;21(11):1501-9. doi: 10.3109/00498259109044400.

Abstract

Codeine O-demethylation to morphine is mediated by cytochrome P450 IID1 (rat), or P450 IID6 (man), and exhibits genetic polymorphism. Thebaine is a precursor in the formation of endogenous morphine and codeine in man, being O-demethylated to oripavine. 2. The objective of the present study was to ascertain whether the O-demethylation of thebaine to oripavine was mediated by cytochrome P450 IID1 in rat liver microsomes. 3. Thebaine O-demethylation showed strain differences in female Sprague-Dawley (SD) and female Dark-Agouti (DA) rats, which serve as a model for the human debrisoquine/sparteine metabolism phenotypes. 4. The total intrinsic clearance of thebaine to oripavine was high (19.7 ml/h per mg protein) in SD rats, indicating that oripavine is a major metabolite of thebaine. A 3-fold lower intrinsic clearance was observed in DA rats (6.7 ml/h per mg protein). 5. Thebaine O-demethylation was inhibited by quinine and known substrates of cytochrome P450 IID1/P450 IID6, supporting the major involvement of cytochrome P450 IID1 in oripavine formation in rats.

摘要

可待因O-去甲基化生成吗啡由细胞色素P450 IID1（大鼠）或P450 IID6（人）介导，并表现出遗传多态性。蒂巴因是人体内内源性吗啡和可待因形成过程中的前体，经O-去甲基化生成阿扑吗啡。2. 本研究的目的是确定大鼠肝微粒体中蒂巴因O-去甲基化生成阿扑吗啡是否由细胞色素P450 IID1介导。3. 在用作人类异喹胍/鹰爪豆碱代谢表型模型的雌性斯普拉格-道利（SD）大鼠和雌性黑褐家鼠（DA）中，蒂巴因O-去甲基化表现出品系差异。4. SD大鼠中蒂巴因生成阿扑吗啡的总内在清除率较高（每毫克蛋白19.7毫升/小时），表明阿扑吗啡是蒂巴因的主要代谢产物。在DA大鼠中观察到的内在清除率低3倍（每毫克蛋白6.7毫升/小时）。5. 奎宁和已知的细胞色素P450 IID1/P450 IID6底物可抑制蒂巴因O-去甲基化，这支持了细胞色素P450 IID1在大鼠阿扑吗啡形成中起主要作用。