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Drug Metabolism and Disposition Fast Forward
First published on May 27, 2008; DOI: 10.1124/dmd.108.021469

0090-9556/08/3609-1745-1752$20.00
DMD 36:1745-1752, 2008

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Species Differences in UDP-Glucuronosyltransferase Activities in Mice and Rats

Hirotada Shiratani, Miki Katoh, Miki Nakajima, and Tsuyoshi Yokoi

Drug Metabolism and Toxicology, Division of Pharmaceutical Sciences, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan

UDP-glucuronosyltransferases (UGTs), expressed in various tissues including liver and intestine, catalyze phase II metabolic biotransformation. There is little information on species differences between mice and rats in UGT activities, especially in intestine. The purpose of the present study was to clarify the species differences between mice and rats in UGT activities using duodenal and liver microsomes. For estradiol 3-O-glucuronidation in duodenal microsomes, the kinetic data in mice were fit to the Hill equation. However, the Hill coefficient was low in rats (n = 1.1), suggesting that rat estradiol 3-O-glucuronidation followed the Michaelis-Menten equation rather than the Hill equation. For 4-nitrophenol (4-NP) O-glucuronidation, the Km values were different between mice and rats. The intrinsic clearance (CLint) values for mycophenolic acid (MPA) O- and morphine 3-O-glucuronidation in male mouse duodenum were 3- and 17-fold lower than those in rat, respectively. In male liver, the CLint values for 4-NP O-, propofol O-, MPA O-, and morphine 3-O-glucuronidation and the CLmax value for 4-methylumbelliferone O-glucuronidation in mice were higher than those in rats. The CLmax value for estradiol 3-O-glucuronidation in mice was lower than that in rats. Also, there were strain differences among C57BL/6J, BALB/c, C3H/HeJ, DBA/2, ddY, and ICR mice in UGT activities in duodenum. We clarified that the species differences in UGT activity evaluated by the CLint or CLmax values in liver and duodenum varied according to the substrate.

Address correspondence to: Dr. Tsuyoshi Yokoi, Drug Metabolism and Toxicology, Division of Pharmaceutical Sciences, Graduate School of Medical Science, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan. E-mail: tyokoi{at}kenroku.kanazawa-u.ac.jp






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