Pavek Petr, Dvorak Zdenek
Department of Pharmacology and Toxicology, Charles University in Prague, Faculty of Pharmacy in Hradec Králové, Heyrovského 1203, 500 05 Hradec Králové, Czech Republic.
Curr Drug Metab. 2008 Feb;9(2):129-43. doi: 10.2174/138920008783571774.
Numerous members of the cytochrome P450 (CYP) superfamily are induced after exposure to a variety of xenobiotics in human liver. We have gained considerable mechanistic insights into these processes in hepatocytes and multiple ligand-activated transcription factors have been identified over the past two decades. Families CYP1, CYP2 and CYP3 involved in xenobiotic metabolism are also expressed in a range of extrahepatic tissues (e.g. intestine, brain, kidney, placenta, lung, adrenal gland, pancreas, skin, mammary gland, uterus, ovary, testes and prostate). Since the expression of the majority of the isoforms appears to be very low in the extrahepatic tissues in comparison with predominant expression in adult liver, the role of the enzymes in overall biotransformation and total body clearance is minor. However, basal expression and up-regulation of extrahepatic CYP enzymes can significantly affect local disposition of xenobiotics or endogenous compounds in peripheral tissues and thus modify their pharmacological/toxicological effects or affect absorption of xenobiotics into systemic circulation. The goal of this review is to critically examine our current understanding of molecular mechanisms involved in induction of xenobiotic metabolizing CYP genes of human families CYP1, CYP2 and CYP3 by exogenous chemicals in extrahepatic tissues. We concentrate on organs such as the intestine, kidney, lung, placenta and skin, which are involved in drug distribution and clearance or are in direct contact with environmental xenobiotics. We also discuss single nucleotide polymorphisms (SNPs) of key CYPs, which at the level of transcription affect expression of the genes in the extrahepatic tissues or are associated with some pathophysiological stages or disorders in the organs.
细胞色素P450（CYP）超家族的众多成员在人类肝脏暴露于多种外源性物质后会被诱导产生。在过去二十年中，我们对肝细胞中的这些过程有了相当多的机制性认识，并鉴定出了多种配体激活的转录因子。参与外源性物质代谢的CYP1、CYP2和CYP3家族也在一系列肝外组织（如肠道、脑、肾、胎盘、肺、肾上腺、胰腺、皮肤、乳腺、子宫、卵巢、睾丸和前列腺）中表达。由于与成年肝脏中的主要表达相比，大多数同工型在肝外组织中的表达似乎非常低，因此这些酶在整体生物转化和全身清除中的作用较小。然而，肝外CYP酶的基础表达和上调可显著影响外源性物质或内源性化合物在周围组织中的局部处置，从而改变它们的药理/毒理作用或影响外源性物质进入体循环的吸收。本综述的目的是批判性地审视我们目前对外源性化学物质在肝外组织中诱导人类CYP1、CYP2和CYP3家族的外源性物质代谢CYP基因所涉及的分子机制的理解。我们专注于肠道、肾脏、肺、胎盘和皮肤等器官，这些器官参与药物分布和清除或与环境外源性物质直接接触。我们还讨论了关键CYP的单核苷酸多态性（SNP），这些多态性在转录水平上影响肝外组织中基因的表达，或与器官中的某些病理生理阶段或疾病相关。
