Shiratani Hirotada, Katoh Miki, Nakajima Miki, Yokoi Tsuyoshi
Division of Pharmaceutical Sciences, Drug Metabolism and Toxicology, Graduate School of Medical Science, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan.
Drug Metab Dispos. 2008 Sep;36(9):1745-52. doi: 10.1124/dmd.108.021469. Epub 2008 May 27.
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 K(m) values were different between mice and rats. The intrinsic clearance (CL(int)) 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 CL(int) values for 4-NP O-, propofol O-, MPA O-, and morphine 3-O-glucuronidation and the CL(max) value for 4-methylumbelliferone O-glucuronidation in mice were higher than those in rats. The CL(max) 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 CL(int) or CL(max) values in liver and duodenum varied according to the substrate.
尿苷二磷酸葡萄糖醛酸基转移酶（UGTs）在包括肝脏和肠道在内的各种组织中表达，催化II相代谢生物转化。关于小鼠和大鼠在UGT活性方面的种属差异，尤其是在肠道中的差异，目前所知甚少。本研究的目的是利用十二指肠和肝脏微粒体阐明小鼠和大鼠在UGT活性方面的种属差异。对于十二指肠微粒体中雌二醇3 - O - 葡萄糖醛酸化反应，小鼠的动力学数据符合希尔方程。然而，大鼠的希尔系数较低（n = 1.1），这表明大鼠的雌二醇3 - O - 葡萄糖醛酸化反应遵循米氏方程而非希尔方程。对于4 - 硝基苯酚（4 - NP）O - 葡萄糖醛酸化反应，小鼠和大鼠的米氏常数（K(m)）值不同。雄性小鼠十二指肠中霉酚酸（MPA）O - 葡萄糖醛酸化反应和吗啡3 - O - 葡萄糖醛酸化反应的内在清除率（CL(int)）值分别比大鼠低3倍和17倍。在雄性肝脏中，小鼠4 - NP O - 、丙泊酚O - 、MPA O - 和吗啡3 - O - 葡萄糖醛酸化反应的CL(int)值以及4 - 甲基伞形酮O - 葡萄糖醛酸化反应的最大清除率（CL(max)）值均高于大鼠。小鼠中雌二醇3 - O - 葡萄糖醛酸化反应的CL(max)值低于大鼠。此外，C57BL/6J小鼠、BALB/c小鼠、C3H/HeJ小鼠、DBA/2小鼠、ddY小鼠和ICR小鼠在十二指肠UGT活性方面也存在品系差异。我们阐明，根据底物不同，肝脏和十二指肠中通过CL(int)或CL(max)值评估的UGT活性种属差异也有所不同。
