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First published on October 29, 2007; DOI: 10.1124/dmd.107.017731

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Received for publication August 6, 2007.
Revised October 12, 2007.
Accepted for publication October 26, 2007.

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

Makoto Osabe 1, Junko Sugatani 1*, Tomoaki Fukuyama 1, Shinichi Ikushiro 2, Akira Ikari 1, Masao Miwa 1

1 School of Pharmaceutical Sciences, University of Shizuoka 2 Biotechnology Research Center, Toyama Prefectural University

* Address correspondence to: E-mail: sugatani{at}u-shizuoka-ken.ac.jp

Abstract

Rats that consumed a high-fat and high-sucrose (HF1) diet or a high-fat (HF2) diet developed hepatic steatosis. The alteration in nutritional status affected hepatic cytochrome P450 and UDP-glucuronosyltransferase (UGT) levels. Messenger RNA and protein levels of UGT1A1 and UGT1A6 in the liver but not the jejunum were increased in male rats fed the HF1 diet. These protein levels did not increase in HF2-fed male rats or HF1-fed female rats. In contrast, the CYP1A2 protein level was decreased in the HF1 but not HF2 diet group, whereas CYP2E1 and CYP4A protein levels were elevated in the HF2 but not HF1 diet group. No significant difference in the Oatp1, Oatp2, Mrp2 or Mrp3 protein levels were found between the standard and HF1 diet groups of male rats. Consumption of the HF1 diet affected the in vivo metabolism of acetaminophen (APAP) such that the area under the APAP-glucuronide plasma concentration – time curve was elevated 2.1-fold in male rats but not female rats. In liver cell nuclei of male rats but not female rats, constitutive androstane receptor (CAR) and proliferator–activated receptor {alpha} (PPAR{alpha}) protein levels were significantly enhanced by intake of the HF1 diet. Additionally, administration of the PPAR{alpha} agonist clofibrate to male rats up-regulated UGT1A1 and UGT1A6 and down-regulated CYP1A2 in the liver. Taken together, these results indicate that nutritional status may gender-specifically influence the expression and activation of CAR and PPAR{alpha} in liver cell nuclei, and this effect appears to be associated with alterations in UGT1A1 and UGT1A6 expression.


Key words: CAR, CYP1A, CYP2E, CYP4, nuclear receptors, peroxisome proliferator-activated receptors, UDP glucuronyltransferases




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