Effect of dicumarol, a Nad(P)h: quinone acceptor oxidoreductase 1 (DT-diaphorase) inhibitor on ubiquinone redox cycling in cultured rat hepatocytes.
Ubiquinol is considered to serve as an endogenous antioxidant. However, the mechanism by which the redox state of intracellular ubiquinone (UQ) is maintained is not well established. The effect of dicumarol, an inhibitor of NAD(P)H: quinone acceptor oxidoreductase 1 (NQO1 = DT-diaphorase, EC 1.6.99.2), on the reduction of UQ in cultured rat hepatocytes was investigated in order to clarify whether or not NQO1 is involved in reducing intracellular UQ. A concentration of 5 microM dicumarol, which does not inhibit cytosolic NADPH-dependent UQ reductase in vitro, was observed to almost completely inhibit NQO1 and thereby to stimulate cytotoxicity of 2-methyl-1,4-naphthoquinone (menadione) in cultured rat hepatocytes. However, 5 microM dicumarol did not inhibit reduction of endogenous UQ-9, as well as exogenous UQ-10 added to the hepatocytes. In addition, it did not stimulate the formation of thiobarbituric acid reactive substances (TBARS) in the hepatocytes. These results suggested that NQO1 is not involved in maintaining UQ in the reduced state in the intact liver cells.
Kishi
Takeo
T
Faculty of Pharmaceutical Sciences and High Technology Research Center, Kobe Gakuin University, Japan. kishi@pharm.kobegakuin.ac.jp
Takahashi
Takayuki
T
Mizobuchi
Shinya
S
Mori
Koichi
K
Okamoto
Tadashi
T
D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D003600:Cytosol / Q000187:drug effects / Q000201:enzymology; D001728:Dicumarol / Q000494:pharmacology*; D042967:Electron Transport Complex I; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D022781:Hepatocytes / Q000187:drug effects* / Q000201:enzymology; D006861:Hydrogen Peroxide / Q000494:pharmacology; D015227:Lipid Peroxidation; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000037:antagonists & inhibitors*; D009247:NADH, NADPH Oxidoreductases / Q000378:metabolism*; D010084:Oxidation-Reduction; D051381:Rats; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism; D014451:Ubiquinone / Q000378:metabolism
D004791:Enzyme Inhibitors; D017392:Thiobarbituric Acid Reactive Substances; D014451:Ubiquinone; D001728:Dicumarol; D006861:Hydrogen Peroxide; D009247:NADH, NADPH Oxidoreductases; D016660:NAD(P)H Dehydrogenase (Quinone); D042967:Electron Transport Complex I