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Drug Metabolism and Disposition Fast Forward
First published on May 23, 2006; DOI: 10.1124/dmd.106.009399

0090-9556/06/3408-1406-1410$20.00
DMD 34:1406-1410, 2006

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N-GLUCURONIDATION OF PERFLUOROOCTANESULFONAMIDE BY HUMAN, RAT, DOG, AND MONKEY LIVER MICROSOMES AND BY EXPRESSED RAT AND HUMAN UDP-GLUCURONOSYLTRANSFERASES

Lin Xu, Daria M. Krenitsky, Andrew M. Seacat1, John L. Butenhoff, Thomas R. Tephly, and M. W. Anders

Department of Pharmacology and Physiology, University of Rochester Medical Center, Rochester, New York (D.M.K., M.W.A.); Merck Research Laboratory at Boston, Boston, Massachusetts (L.X.); 3M Medical Department, Corporate Toxicology, 3M Center 220-2E-02, St. Paul, Minnesota (A.M.S., J.L.B.); and Department of Pharmacology, The University of Iowa, Iowa City, Iowa (T.R.T.)

N-Alkylperfluorooctanesulfonamides have been used in a range of industrial and commercial applications. Perfluorooctanesulfonamide (FOSA) is a major metabolite of N-alkylperfluorooctanesulfonamides and has a long half-life in animals and in the environment and is biotransformed to FOSA N-glucuronide. The objective of this study was to identify and characterize the human and experimental animal liver UDP-glucuronosyltransferases (UGTs) that catalyze the N-glucuronidation of FOSA. The results showed that pooled human liver and rat liver microsomes had high N-glucuronidation activities. Expressed rat UGT1.1, UGT2B1, and UGT2B12 in HK293 cells catalyzed the N-glucuronidation of FOSA but at rates that were lower than those observed in rat liver microsomes. Of the 10 expressed human UGTs (1A1, 1A3, 1A4, 1A6, 1A9, 2B4, 2B7, 2B15, and 2B17) studied, only hUGT2B4 and hUGT2B7 catalyzed the N-glucuronidation of FOSA. The kinetics of N-glucuronidation of FOSA by rat liver microsomes and by hUGT2B4/7 was consistent with a single-enzyme Michaelis-Menten model, whereas human liver microsomes showed sigmoidal kinetics. These data show that rat liver UGT1.1, UGT2B1, and UGT2B12 catalyze the N-glucuronidation of FOSA, albeit at low rates, and that hUGT2B4 and hUGT2B7 catalyze the N-glucuronidation of FOSA.

Address correspondence to: M. W. Anders, Department of Pharmacology and Physiology, University of Rochester Medical Center, 601 Elmwood Avenue, Box 711, Rochester, NY 14642. E-mail: mw_anders{at}urmc.rochester.edu




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