CYP2D表达与功能调控及其在药物和内源性物质处置中的作用

Expression and functional regulation of CYP2D and its role in drug and endogenous substance disposal

CYP2D属于细胞色素P450(CYP450)家族,是一类重要的药物代谢酶。CYP2D介导约25%的临床药物代谢,包括抗抑郁药、抗心律失常药、镇痛药、抗肿瘤药等;同时其活性也会被某些药物,如氟西汀、普萘洛尔等抑制,进而导致与CYP2D底物药物联合使用时,药物不良反应的发生或加重。此外,CYP2D可介导脑内部分内源性神经递质,如多巴胺和5-羟色胺合成的替代途径和维持神经类固醇,如四氢孕酮的脑内稳态。这提示CYP2D可能在中枢神经系统的调节中发挥作用。研究表明,性激素以及过氧化物酶体增殖物激活受体(PPARs)、法尼类X受体(FXR)、肝细胞核因子4α(HNF4α)等核受体可以调控CYP2D mRNA水平和蛋白表达。多种生理和病理因素可能会改变CYP2D的表达和功能,进而影响其底物药物的处置和药效学。本文对CYP2D的结构、功能、调控因素以及生理和疾病状态下CYP2D表达和功能的改变、CYP2D抑制剂等研究进展进行综述,为临床更安全及合理用药提供参考。

CYP2D,a member of the Cytochrome P450 family,is an important class of drug-metabolizing enzymes.CYP2D mediates about 25%of clinical drug metabolism,including antidepressants,antiarrhythmics,analgesics,antineoplastic drugs etc.At the same time,its activity is also inhibited by certain drugs,such as fluoxetine,propranolol,etc.,which lead to the occurrence or aggravation of adverse drug reactions when combined with CYP2D substrate drugs.In addition,CYP2D mediates alternative pathways for the synthesis of some endogenous neurotransmitters in the brain,such as dopamine and serotonin,and maintains homeostasis of neurosteroids such as allopregnanolone in the brain.This suggests that CYP2D may play a role in the regulation of the central nervous system.Studies have shown that sex hormones and nuclear receptors including PPARs,FXR,and HNF4αcan regulate mRNA and protein expressions of CYP2D.A variety of physiological and pathological factors may alter the expression and function of CYP2D,which in turn affects the disposal and pharmacodynamics of its substrate drugs.This review provides an overview of the structure,function,regulatory factor,as well as the changes of CYP2D expression and function in physiological and disease state.