title: Reduction of cytotoxic p-quinone metabolites of tert-butylhydroquinone by human aldo-keto reductase (AKR) 1B10.
abstract: 2-tert-Butylhydroquinone (BHQ), an antioxidant used as a food additive, exhibits an anticancer effect, whereas it is carcinogenic in rodents at high doses. BHQ is metabolized into cytotoxic tert-butylquinone (BQ), which is further converted to 6-tert-butyl-2,3-epoxy-4-hydroxy-5-cyclohexen-1-one (TBEH) through 6-tert-butyl-2,3-epoxy-4-benzoquinone (TBE), which induces chromosomal aberration. The reductases for BQ and TBE may be protective against the toxicity of the two p-quinones, but the responsible human enzymes remain unidentified. In this study, we compared the ability of 12 human recombinant enzymes in the aldo-keto reductase (AKR) and short-chain dehydrogenase/reductase superfamilies to reduce BQ and TBE. Among them, AKR1B10 was the most efficient catalyst of the stoichiometric two-electron reduction of BQ and TBE into BHQ and TBEH, respectively. BQ and TBE are more cytotoxic towards endothelial cells than BHQ and TBEH, and their cytotoxicity was decreased by the overexpression of AKR1B10 in the cells. Additionally, AKR1B10 gene expression in human HCT116 cells was up-regulated by treatments with BHQ, BQ and TBE. These results suggest a role for the enzyme in protection at least against the toxicity of the two p-quinone metabolites of BHQ.
authors.affiliation: Gifu Pharmaceutical University, Gifu, Japan. matsunagat@gifu-pu.ac.jp
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Matsunaga
authors.forename: Satoshi
authors.initials: S
authors.lastname: Endo
authors.forename: Mayuko
authors.initials: M
authors.lastname: Takemura
authors.forename: Midori
authors.initials: M
authors.lastname: Soda
authors.forename: Keiko
authors.initials: K
authors.lastname: Yamamura
authors.forename: Kazuo
authors.initials: K
authors.lastname: Tajima
authors.forename: Takeshi
authors.initials: T
authors.lastname: Miura
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Terada
authors.forename: Ossama
authors.initials: O
authors.lastname: El-Kabbani
authors.forename: Akira
authors.initials: A
authors.lastname: Hara
mesh_terms: D000449:Aldehyde Reductase / Q000235:genetics / Q000378:metabolism*; D000074408:Aldo-Keto Reductases; D000975:Antioxidants / Q000378:metabolism; D016227:Benzoquinones / Q000378:metabolism; D002384:Catalysis; D045744:Cell Line, Tumor; D042783:Endothelial Cells; D045325:HCT116 Cells; D006801:Humans; D006873:Hydroquinones / Q000378:metabolism*; D010088:Oxidoreductases / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D015854:Up-Regulation
chemical_list: D000975:Antioxidants; D016227:Benzoquinones; D006873:Hydroquinones; D012333:RNA, Messenger; C091758:6-tert-butyl-2,3-epoxy-1,4-benzoquinone; C018855:2-tert-butylhydroquinone; D010088:Oxidoreductases; C120471:AKR1B10 protein, human; D000074408:Aldo-Keto Reductases; D000449:Aldehyde Reductase; C051290:2-tert-butyl-4-quinone