Abstract
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 α (PPARα; 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 PPARα 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.
Footnotes
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This study was supported by National Institutes of Health Grant ES-03192.
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Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
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doi:10.1124/dmd.106.010397.
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ABBREVIATIONS: UGT, UDP-glucuronosyltransferase; P450, cytochrome P450; AhR, aryl hydrocarbon receptor; CAR, constitutive androstane receptor; PXR, pregnane X receptor; PPARα, peroxisome proliferator-activated receptor α; Nrf2, nuclear factor erythroid 2 (NF-E2)-related factor 2; MEI, microsomal enzyme inducer; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin; PCB126, polychlorinated biphenyl congener 126; PCB99, polychlorinated biphenyl congener 99; PCN, pregnenolone-16α-carbonitrile; DEHP, di-(2-ethylhexyl)phthalate; PFDA, perfluorodecanoic acid; PP, peroxisome proliferators; XRE, xenobiotic response element.
- Received April 10, 2006.
- Accepted July 12, 2006.
- The American Society for Pharmacology and Experimental Therapeutics
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