Received for publication April 11, 2006.
Revised July 12, 2006.
Accepted for publication July 12, 2006.

Induction of Rat UDP-Glucuronosyltransferases in Liver and Duodenum by Microsomal Enzyme Inducers That Activate Various Transcriptional Pathways

Abstract

Microsomal enzyme inducers (MEIs) up-regulate phase-I biotransformation enzymes, most notably cytochrome P450s (CYPs). 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 a (PPARa; CYP4A inducers). Other mechanisms include transcription factors aryl hydrocarbon receptor (AhR; CYP1A inducers), and 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 PPARa 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, though no one transcriptional pathway dominated. In duodenum, MEIs had minimal effects on UGT expression.

Key words: enzyme induction, induction, nuclear receptors, UDP glucuronyltransferases

This article has been cited by other articles:

				M. Osabe, J. Sugatani, T. Fukuyama, S.-i. Ikushiro, A. Ikari, and M. Miwa Expression of Hepatic UDP-Glucuronosyltransferase 1A1 and 1A6 Correlated with Increased Expression of the Nuclear Constitutive Androstane Receptor and Peroxisome Proliferator-Activated Receptor {alpha} in Male Rats Fed a High-Fat and High-Sucrose Diet Drug Metab. Dispos., February 1, 2008; 36(2): 294 - 302. [Abstract] [Full Text] [PDF]

				L. M. Aleksunes and J. E. Manautou Emerging Role of Nrf2 in Protecting Against Hepatic and Gastrointestinal Disease Toxicol Pathol, June 1, 2007; 35(4): 459 - 473. [Abstract] [Full Text] [PDF]

				E. G. van de Kerkhof, I. A. M. de Graaf, M. H. de Jager, and G. M. M. Groothuis Induction of Phase I and II Drug Metabolism in Rat Small Intestine and Colon in Vitro Drug Metab. Dispos., June 1, 2007; 35(6): 898 - 907. [Abstract] [Full Text] [PDF]