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Drug Metabolism and Disposition Fast Forward
First published on May 30, 2008; DOI: 10.1124/dmd.108.020610

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Received for publication March 3, 2008.
Revised May 28, 2008.
Accepted for publication May 29, 2008.

Androgen Regulation of Renal UGT1A1 in Rats

Stephan T Stern 1, Melanie N Tallman 2, Kristini K. Miles 3, Joseph K. Ritter 4, Philip C. Smith 5*

1 NCI, NIH, Frederick, MD 2 Gilead Pharmaceuticals 3 Virginia Commonwealth U, Richmond 4 Virginia Commonwealth U, Richmond, VA 5 UNC Chapel Hill, NC

* Address correspondence to: E-mail: pcs{at}email.unc.edu

Abstract

Many phase I and II enzymes are under hormonal regulation, resulting in sex-related expression patterns. This sex-related enzyme expression can result in differential metabolism of physiologically active endogenous substances, altered xenobiotic clearance, as well as differences in susceptibility to drug toxicities. Treatment of female Sprague-Dawley (SD) rats with 5 mg testosterone propionate/kg/d, 2 mL/kg SC for 8 days resulted in induction of renal uridine diphosphoglucuronosyltransferase 1A1 (UGT1A1), as determined by immunoblot and probe substrate activity. Glucuronidation activity for mycophenolic acid, a substrate for rat UGT1A1, 1A6 and 1A7, was significantly elevated approximately two-fold in renal microsomes from testosterone propionate treated animals. Protein expression of rat UGT1A1 was also dramatically increased, while 1A6 and 1A7 remained unchanged as a result of treatment. Male SD rats were determined to express greater renal UGT1A1 than age-matched female rats. These data support the androgen regulation of rat renal UGT 1A1.


Key words: gender differences, glucuronidation, phase II drug metabolism, renal elimination, UDP glucuronyltransferases




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