Homeostatic control of xeno- and endobiotics in the drug-metabolizing enzyme system

被引:38
作者
Bock, Karl Walter [1 ]
机构
[1] Univ Tubingen, Inst Expt & Clin Pharmacol & Toxicol, Dept Toxicol, D-72074 Tubingen, Germany
关键词
CYP1; UGT1; Ah receptor; FICZ; Bilirubin; Phytochemicals; ARYL-HYDROCARBON RECEPTOR; PREGNANE-X-RECEPTOR; PHENOL UDP-GLUCURONOSYLTRANSFERASES; CONSTITUTIVE ANDROSTANE RECEPTOR; AH RECEPTOR; NUCLEAR RECEPTORS; TRANSCRIPTIONAL REGULATION; MEDIATED INDUCTION; DIOXIN RECEPTOR; CYP1A2; GENES;
D O I
10.1016/j.bcp.2014.04.009
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
Drug-metabolizing Phase I and II enzyme families, drug transporters (Phase III) and their ligandactivated transcription factors probably evolved as a system involved in homeostatic control of lipophilic endobiotics and detoxification of xenobiotics. The review is focused on CYP, UGT enzymes and the Ah receptor as transcription factor. The hypothesis of a system is supported by (i) coordinate regulation of subsets of these enzyme families and transporters by transcription factors including the AhR, and (ii) feedback loops between endobiotic AhR agonists and substrates of major catabolic target genes/proteins; for example, 6-formylindolo[3,2-blcarbazole as substrate of CYP1A1, and bilirubin, as substrate of UGT1A1. In the latter case the AhR is one of multiple transcription factors contributing to bilirubin homeostasis. Interestingly, xenobiotics including dietary phytochemicals, products of microbiota, ubiquitous environmental pollutants such as benzo[a]pyrene may also have shaped this system in intestinal epithelia during millions of years of evolution. Most lipophilic drugs are metabolized by the same system since drug-metabolizing enzymes are broad substrate spectrum enzymes. Better understanding of this system may lead to generation of drugs with desirable therapeutic properties. (C) 2014 Elsevier Inc. All rights reserved.
引用
收藏
页码:1 / 6
页数:6
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