Neve Etienne P A, Ingelman-Sundberg Magnus
Karolinska Institutet, Section of Pharmacogenetics, Department of Physiology and Pharmacology, Nanna Svartz väg 2, 171 77 Stockholm, Sweden.
Curr Opin Drug Discov Devel. 2010 Jan;13(1):78-85.
Cytochrome P450 (CYP) is a large family of well-conserved integral membrane proteins localized primarily in the membrane of the endoplasmic reticulum (ER), where these enzymes metabolize a variety of both endogenous and exogenous compounds. It has become apparent that these microsomal CYP proteins are also present in other cellular compartments, such as the cell surface and in mitochondria, where the enzymes display catalytic activity toward CYP-specific substrates, in some cases with altered substrate specificity. CYP-drug adducts exposed at the cell surface are important mediators of idiosyncratic drug toxicities. Therefore, understanding the molecular mechanisms responsible for directing these microsomal CYPs to other, non-ER cellular compartments is important. These alternatively localized CYPs should be considered as possible drug targets and as important factors during drug discovery and development, as the detoxification capacity is lower in the compartments where such CYP proteins are located. This review discusses the mechanisms of intracellular CYP transport, and the implications of the presence of CYP proteins in extra-ER compartments for drug metabolism and toxicity.
细胞色素P450（CYP）是一个高度保守的膜整合蛋白大家族，主要定位于内质网（ER）膜上，这些酶在那里代谢多种内源性和外源性化合物。很明显，这些微粒体CYP蛋白也存在于其他细胞区室，如细胞表面和线粒体中，在这些地方，这些酶对CYP特异性底物具有催化活性，在某些情况下底物特异性会发生改变。细胞表面暴露的CYP-药物加合物是特异质性药物毒性的重要介质。因此，了解将这些微粒体CYP导向其他非内质网细胞区室的分子机制很重要。这些定位不同的CYP应被视为可能的药物靶点以及药物发现和开发过程中的重要因素，因为在这些CYP蛋白所在的区室中解毒能力较低。本综述讨论了细胞内CYP转运的机制，以及内质网外区室中CYP蛋白的存在对药物代谢和毒性的影响。
