Identification of human UDP-glucuronosyltransferase isoform(s) responsible for the C-glucuronidation of phenylbutazone.
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.
Nishiyama
Takahito
T
Department of Drug Metabolism and Molecular Toxicology, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji-shi, Tokyo, Japan.
Kobori
Tomihiro
T
Arai
Kouji
K
Ogura
Kenichiro
K
Ohnuma
Tomokazu
T
Ishii
Kazuo
K
Hayashi
Kenichiro
K
Hiratsuka
Akira
A
D002478:Cells, Cultured; D020719:Glucuronides / Q000378:metabolism*; D014453:Glucuronosyltransferase / Q000032:analysis / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D007583:Jejunum / Q000378:metabolism*; D007668:Kidney / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D008862:Microsomes, Liver / Q000378:metabolism*; D010653:Phenylbutazone / Q000378:metabolism*
D020719:Glucuronides; D007527:Isoenzymes; D014453:Glucuronosyltransferase; D010653:Phenylbutazone