title: UDP-glucuronosyltransferases 1A6 and 1A10 catalyze reduced menadione glucuronidation.
abstract: Menadione (2-methyl-1,4-naphthoquine), also known as vitamin K3, has been widely used as a model compound in the field of oxidative stress-related research. The metabolism of menadione has been studied, and it is known that menadione undergoes a two-electron reduction by NAD(P)H:Quinone oxidoreductase 1 (NQO1) after which the reduced form of menadione (2-methyl-1,4-naphthalenediol, menadiol) is glucuronidated and excreted in urine. To investigate which human UDP-glucuronosyltransferase (UGT) isoforms participate in the glucuronidation of menadiol reduced by NQO1 from menadione, we first constructed heterologously expressed NQO1 in Sf9 cells and tested the menadiol glucuronidating activity of 16 human recombinant UGT isoforms. Of the 16 UGT isoforms, UGTs 1A6, 1A7, 1A8, 1A9, and 1A10 catalyzed menadiol glucuronidation, and, of these, UGTs 1A6 and 1A10 catalyzed menadiol glucuronidation at much higher rates than the other UGTs. Menadiol was regioselectively glucuronidated in the manner of 4-position>1-position by UGTs 1A7, 1A8, 1A9, and 1A10. In contrast to these UGTs, only UGT1A6 exhibited 1-menadiol-preferential glucuronidating activity. The results suggest possible detoxification pathways for quinones via NQO1 reduction followed by UGT glucuronidation.
authors.affiliation: Department of Drug Metabolism and Molecular Toxicology, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji-shi, Tokyo 192-0392, Japan.
authors.forename: Takahito
authors.initials: T
authors.lastname: Nishiyama
authors.forename: Tomokazu
authors.initials: T
authors.lastname: Ohnuma
authors.forename: Yuu
authors.initials: Y
authors.lastname: Inoue
authors.forename: Takehiko
authors.initials: T
authors.lastname: Kishi
authors.forename: Kenichiro
authors.initials: K
authors.lastname: Ogura
authors.forename: Akira
authors.initials: A
authors.lastname: Hiratsuka
mesh_terms: D000818:Animals; D002384:Catalysis; D002478:Cells, Cultured; D020723:Glucuronic Acid / Q000378:metabolism*; D014453:Glucuronosyltransferase / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008658:Inactivation, Metabolic; D007583:Jejunum / Q000201:enzymology / Q000648:ultrastructure; D008099:Liver / Q000201:enzymology / Q000648:ultrastructure; D008861:Microsomes / Q000201:enzymology; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D024483:Vitamin K 3 / Q000378:metabolism*
chemical_list: D011994:Recombinant Proteins; D024483:Vitamin K 3; D020723:Glucuronic Acid; D016660:NAD(P)H Dehydrogenase (Quinone); C447479:NQO1 protein, human; C110655:UDP-glucuronosyltransferase, UGT1A6; C476725:bilirubin uridine-diphosphoglucuronosyl transferase 1A10; D014453:Glucuronosyltransferase