Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences (T.K., Y.F., K.O., S.G., T.F., M.N.), and WPI Nano Life Science Institute (T.F., M.N.), Kanazawa University, Kakuma-machi, Kanazawa, Japan.
Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences (T.K., Y.F., K.O., S.G., T.F., M.N.), and WPI Nano Life Science Institute (T.F., M.N.), Kanazawa University, Kakuma-machi, Kanazawa, Japan
Drug Metab Dispos. 2019 Jan;47(1):38-44. doi: 10.1124/dmd.118.083287. Epub 2018 Nov 2.
UDP-glucuronosyltransferases (UGTs) catalyze the glucuronidation of numerous endogenous and exogenous compounds to facilitate their excretion from the body. Because rats are commonly used in nonclinical studies, information regarding UGT species differences between rats and humans would be helpful for understanding human pharmacokinetics. In this study, we determined the absolute mRNA expressions of Ugt isoforms in the liver and small intestine of male and female Sprague-Dawley, Fischer 344, and Wistar rats. The sum of the mRNA levels of Ugt isoforms expressed in the liver was significantly ( < 0.005) higher than that in the small intestine regardless of the strain and sex. Ugt2b mRNA levels represented approximately 80% of total Ugt mRNA levels in the liver, whereas Ugt1a mRNA levels accounted for almost 90% in the small intestine. Ugt2b2 mRNA was specifically expressed in Wistar rat liver, resulting in 2-fold higher expression of total hepatic Ugt mRNA in Wistar rats than that in the other strains. Wistar rats showed prominently higher Ugt2b3 and Ugt2b8 mRNA levels in the small intestine than the other strains. The difference between sexes was remarkable with regard to hepatic Ugt1a10 in any of the strains, although slight differences between sexes were also observed in multiple Ugt isoforms. Taken together, this study revealed sex and strain differences in mRNA levels of rat Ugts. The data shown here would be useful for the selection of rat strains in nonclinical studies.
UDP-葡萄糖醛酸转移酶 (UGTs) 催化许多内源性和外源性化合物的葡萄糖醛酸化，以促进它们从体内排出。由于大鼠通常用于非临床研究，因此了解大鼠和人类之间 UGT 种属差异的信息将有助于理解人类药代动力学。在这项研究中，我们测定了雄性和雌性 Sprague-Dawley、Fisher 344 和 Wistar 大鼠肝和小肠中 Ugt 同工型的绝对 mRNA 表达。无论品系和性别如何，肝脏中表达的 Ugt 同工型的 mRNA 水平之和均显著高于小肠（<0.005）。Ugt2b mRNA 水平代表肝脏中总 Ugt mRNA 水平的约 80%，而 Ugt1a mRNA 水平在小肠中几乎占 90%。Ugt2b2 mRNA 特异性表达于 Wistar 大鼠肝脏，导致 Wistar 大鼠肝脏总 Ugt mRNA 表达水平比其他品系高 2 倍。Wistar 大鼠小肠中 Ugt2b3 和 Ugt2b8 mRNA 水平明显高于其他品系。任何品系的雄性和雌性大鼠肝脏 Ugt1a10 之间的性别差异均很显著，尽管在多个 Ugt 同工型中也观察到了轻微的性别差异。总之，这项研究揭示了大鼠 Ugt 的 mRNA 水平存在性别和品系差异。此处显示的数据将有助于非临床研究中大鼠品系的选择。
