Shelby M K, Klaassen C D
Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160-7417, USA.
Drug Metab Dispos. 2006 Oct;34(10):1772-8. doi: 10.1124/dmd.106.010397. Epub 2006 Jul 19.
Microsomal enzyme inducers (MEIs) up-regulate phase I biotransformation enzymes, most notably cytochromes P450. Transcriptional up-regulation by MEIs occurs through at least three nuclear receptor mechanisms: constitutive androstane receptor (CAR; CYP2B inducers), pregnane X receptor (PXR; CYP3A inducers), and peroxisome proliferator-activated receptor alpha (PPARalpha; CYP4A inducers). Other mechanisms include transcription factors aryl hydrocarbon receptor (AhR; CYP1A inducers), and nuclear factor erythroid 2 (NF-E2)-related factor 2 (Nrf2; NADPH-quinone oxidoreductase inducers). UDP-glucuronosyltransferases (UGTs) are phase II biotransformation enzymes that are predominantly expressed in liver and intestine. MEIs increase UGT activity; however, transcriptional regulation of individual UGT isoforms is not completely understood. The purpose of this study was to examine inducibility of individual UGT isoforms and potential mechanisms of transcriptional regulation in rat liver and duodenum. UGT mRNA levels were assessed in liver and duodenum of rats treated with MEIs that activate various transcriptional pathways. All four CAR activators induced UGT2B1 in liver, but not duodenum. UGT1A1, 1A5, 1A6, and 2B12 were induced by at least two CAR activators in liver only. Two PXR ligands induced UGT1A2, but only in duodenum. Two PPARalpha ligands induced UGT1A1 and 1A3 in liver only. AhR ligands induced UGT1A6 and 1A7 in liver, but not duodenum. Nrf2 activators increased UGT2B3 and 2B12 in both liver and duodenum, and UGT1A6, 1A7, and 2B1 in liver only. In summary, only UGT1A2 and 1A8 were not inducible in liver by MEIs. MEIs differentially regulate hepatic expression of individual UGT isoforms, although no one transcriptional pathway dominated. In duodenum, MEIs had minimal effects on UGT expression.
微粒体酶诱导剂（MEIs）上调I相生物转化酶，最显著的是细胞色素P450。MEIs的转录上调通过至少三种核受体机制发生：组成型雄甾烷受体（CAR；CYP2B诱导剂）、孕烷X受体（PXR；CYP3A诱导剂）和过氧化物酶体增殖物激活受体α（PPARα；CYP4A诱导剂）。其他机制包括转录因子芳烃受体（AhR；CYP1A诱导剂）和核因子红细胞2（NF-E2）相关因子2（Nrf2；NADPH-醌氧化还原酶诱导剂）。尿苷二磷酸葡萄糖醛酸基转移酶（UGTs）是II相生物转化酶，主要在肝脏和肠道中表达。MEIs增加UGT活性；然而，单个UGT同工型的转录调控尚未完全明确。本研究的目的是研究大鼠肝脏和十二指肠中单个UGT同工型的可诱导性以及转录调控的潜在机制。在用激活各种转录途径的MEIs处理的大鼠的肝脏和十二指肠中评估UGT mRNA水平。所有四种CAR激活剂均诱导肝脏中的UGT2B1，但不诱导十二指肠中的UGT2B1。UGT1A1、1A5、1A6和2B12仅在肝脏中被至少两种CAR激活剂诱导。两种PXR配体仅在十二指肠中诱导UGT1A2。两种PPARα配体仅在肝脏中诱导UGT1A1和1A3。AhR配体在肝脏中诱导UGT1A6和1A7，但不在十二指肠中诱导。Nrf2激活剂在肝脏和十二指肠中均增加UGT2B3和2B12，在肝脏中仅增加UGT1A6、1A7和2B1。总之，MEIs在肝脏中仅UGT1A2和1A8不可诱导。MEIs差异调节单个UGT同工型的肝脏表达，尽管没有一种转录途径占主导地位。在十二指肠中，MEIs对UGT表达的影响最小。
