Nishiyama Takahito, Kobori Tomihiro, Arai Kouji, Ogura Kenichiro, Ohnuma Tomokazu, Ishii Kazuo, Hayashi Kenichiro, Hiratsuka Akira
Department of Drug Metabolism and Molecular Toxicology, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji-shi, Tokyo, Japan.
Arch Biochem Biophys. 2006 Oct 1;454(1):72-9. doi: 10.1016/j.abb.2006.07.010. Epub 2006 Aug 7.
Glucuronidation is a major metabolic pathway in the biotransformation of many xenobiotics and endogeneous compounds. There have been many studies on the formation of O-, N- or S-glucuronides and identification of the UDP-glucuronosyltransferase (UGT) isoforms responsible for the formation of these glucuronides. However, there is no information available on which UGT isoform(s) catalyzes C-glucuronidation. In the present study, 16 human UGTs (UGTs 1A1, 1A3, 1A4, 1A5, 1A6, 1A7, 1A8, 1A9, 1A10, 2B4, 2B7, 2B10, 2B11, 2B15, 2B17 and 2B28) were cloned and expressed in baculovirus-infected insect cells and investigated to determine their C-glucuronidating activity toward phenylbutazone (PB). Among the UGT isoforms investigated, only UGT1A9 catalyzed PB C-glucuronidation. Human liver and kidney microsomes, which are well known to express UGT1A9, had C-glucuronidating activity toward PB. However, the jejunum, which did not express UGT1A9, had no C-glucuronidating activity. These results demonstrate for the first time that PB C-glucuronidation is catalyzed by only UGT1A9.
葡萄糖醛酸化是许多外源性和内源性化合物生物转化中的主要代谢途径。关于O-、N-或S-葡萄糖醛酸苷的形成以及负责这些葡萄糖醛酸苷形成的尿苷二磷酸葡萄糖醛酸基转移酶（UGT）同工型的鉴定，已经有很多研究。然而，关于哪种UGT同工型催化C-葡萄糖醛酸化，尚无相关信息。在本研究中，克隆了16种人UGT（UGT 1A1、1A3、1A4、1A5、1A6、1A7、1A8、1A9、1A10、2B4、2B7、2B10、2B11、2B15、2B17和2B28）并在杆状病毒感染的昆虫细胞中表达，研究它们对保泰松（PB）的C-葡萄糖醛酸化活性。在所研究的UGT同工型中，只有UGT1A9催化PB的C-葡萄糖醛酸化。众所周知表达UGT1A9的人肝微粒体和肾微粒体对PB具有C-葡萄糖醛酸化活性。然而，不表达UGT1A9的空肠没有C-葡萄糖醛酸化活性。这些结果首次证明PB的C-葡萄糖醛酸化仅由UGT1A9催化。
