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Drug Metabolism and Disposition Fast Forward
First published on January 13, 2006; DOI: 10.1124/dmd.105.006601

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Received for publication July 21, 2005.
Revised December 19, 2005.
Accepted for publication January 12, 2006.

Effect of Chronic Renal Insufficiency on Hepatic and Renal UDP-Glucuronyltransferases in Rats

Chuanhui Yu 1, Joseph K Ritter 2, Richard J Krieg 1, Bhaskar Rege 1, Thomas Howard Karnes 1, Mohamadi A Sarkar 3*

1 Virginia Commonwealth University 2 Virginian Commonwealth University 3 Philip Morris USA

* Address correspondence to: E-mail: mohamadi.sarkar{at}pmusa.com

Abstract

Significant evidence exists regarding altered CYP450 enzymes in chronic renal insufficiency (CRI), although none exists for the Phase II enzymes. The objective of this study was to investigate the effect of CRI on hepatic and renal UDP-glucuronyltransferase (UGT) enzymes. Three groups of rats were included: CRI induced by the 5/6th nephrectomy model, control and control pair-fed (CPF) rats. UGT activities were determined in liver and kidney microsomes by the 3- and 17-glucuronidation of {beta}-estradiol (E2-3G and E2-17G), glucuronidation of 4-methylumbelliferone (4-MUG) and 3-glucuronidation of morphine (M3G). UGT isoforms responsible for these catalytic activities were screened using recombinant rat UGT1A1, UGT1A2, UGT1A3, UGT1A7, UGT2B2, UGT2B3, and UGT2B8. UGT protein levels were examined by Western blot analysis using polyclonal antibodies. There was no significant difference between CRI and CPF rats in hepatic and/or renal E2-3G (UGT1A1), E2-17G (UGT2B3), 4-MUG (UGT1A6), and M3G (UGT2B1) formation. Formation of E2-17G and 4-MUG in the liver, and E2-3G and 4-MUG in the kidney was significantly reduced (p<0.05) in CPF and CRI rats, as compared to control rats. The downregulated glucuronidation activities were accompanied by corresponding reductions in protein content of specific UGT isoforms. These results suggest that CRI does not appear to influence the protein levels or catalytic activity of most of the major hepatic or renal UGT enzymes. The observed downregulation of hepatic and renal UGTs in CRI and CPF rats could be caused by restricted food intake in these groups of rats. (Key word: CRI, food restriction, drug metabolism, UGT)


Key words: chronic renal failure, drug clearance, extrahepatic drug metabolism, glucuronidation, phase II drug metabolism


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E. Simard, J. Naud, J. Michaud, F. A. Leblond, A. Bonnardeaux, C. Guillemette, E. Sim, and V. Pichette
Downregulation of Hepatic Acetylation of Drugs in Chronic Renal Failure
J. Am. Soc. Nephrol., July 1, 2008; 19(7): 1352 - 1359.
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