Induction of drug metabolism enzymes and transporters by oltipraz in rats

• Published in: Journal of biochemical and molecular toxicology 2008-03, Vol.22 (2), p.128-135
• Main Authors: Merrell, Matthew D., Augustine, Lisa M., Slitt, Angela L., Cherrington, Nathan J.
• Format: Article
• Language: English
• Subjects: Animals; Blotting, Western; CAR; Carrier Proteins - biosynthesis; Cytochrome P-450 Enzyme System - biosynthesis; Drug Disposition; Drug Interactions; Enzyme Induction; Female; Liver - drug effects; Liver - enzymology; Male; Metabolic Enzymes; NAD(P)H Dehydrogenase (Quinone) - biosynthesis; Nrf2; Oltipraz; Pharmaceutical Preparations - metabolism; Pyrazines - toxicity; Rats; Rats, Inbred WKY; Rats, Sprague-Dawley; Sex Characteristics
• ISSN: 1095-6670; 1099-0461
• DOI: 10.1002/jbt.20225

Coordinate regulation of Phase‐I and ‐II enzymes with xenobiotic transporters has been shown after treatment with microsomal enzyme inducers. The chemopreventive agent oltipraz (OPZ) induces Phase‐I and ‐II drug‐metabolizing enzymes such as CYP2B and NQO1. The purpose of this study was to examine the regulation of drug‐metabolizing enzymes and transporters in response to OPZ treatment and to investigate a potential role for constitutive androstane receptor (CAR) in OPZ‐mediated induction. Sprague‐Dawley rats treated with OPZ exhibited increased mRNA and protein levels of both Nqo1 and Cyp2b1/2 by 24 h. To examine whether OPZ activates transporter gene expression via CAR, sexually dimorphic male and female Wistar‐Kyoto (WKY) rats were treated with OPZ and mRNA levels quantified by bDNA signal amplification. OPZ induced Ugt1a6 and Ugt2b1 in males significantly higher than in females, indicating a CAR‐dependent mechanism of induction. However, OPZ induced microsomal epoxide hydrolase, NAD(P)H quinone oxidoreductase, and Cyp3a1/23 equally in both genders, indicating a CAR‐independent mechanism of induction of these genes. Similarly, the transporters Mdr1a, Mdr1b, Mrp3, and Mrp4 were induced by OPZ without any apparent difference between genders. In summary, OPZ coordinately increases multiple hepatic xenobiotic transporter mRNA levels, along with Phase‐I and ‐II enzymes some of which may occur through CAR‐dependent mechanisms. © 2008 Wiley Periodicals, Inc. J Biochem Mol Toxicol 22:128–135, 2008; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jbt.20225