title: Hepatic glutathione contributes to attenuation of thioacetamide-induced hepatic necrosis due to suppression of oxidative stress in diet-induced obese mice.
abstract: We previously reported that hepatic necrosis induced by thioacetamide (TA), a hepatotoxicant, was attenuated in mice fed a high-fat diet (HFD mice) in comparison with mice fed a normal rodent diet (ND mice). In this study, we focused on investigation of the mechanism of the attenuation. Hepatic content of thiobarbituric acid reactive substances (TBARS), an oxidative stress marker, significantly increased in ND mice at 24 and 48 hr after TA administration in comparison to that in vehicle-treated ND mice. At these time points, severe hepatic necrosis was observed in ND mice. Treatment with an established antioxidant, butylated hydroxyanisole, attenuated the TA-induced hepatic necrosis in ND mice. In contrast, in HFD mice, hepatic TBARS content did not increase, and hepatic necrosis was attenuated in comparison with ND mice at 24 and 48 hr after TA dosing. Metabolomics analysis regarding hepatic glutathione, a biological antioxidant, revealed decreased glutathione and changes in the amount of glutathione metabolism-related metabolites, such as increased ophtalmate and decreased cysteine, and this indicated activation of glutathione synthesis and usage in HFD mice. Finally, after treatment with L-buthionine-S,R-sulfoxinine, an inhibitor of glutathione synthesis, TA-induced hepatic necrosis was enhanced and hepatic TBARS contents increased after TA dosing in HFD mice. These results suggested that activated synthesis and usage of hepatic GSH, which suppresses hepatic oxidative stress, is one of the factors that attenuate TA-induced hepatic necrosis in HFD mice.
authors.affiliation: Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd.
authors.forename: Makoto
authors.initials: M
authors.lastname: Shirai
authors.forename: Miho
authors.initials: M
authors.lastname: Matsuoka
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Makino
authors.forename: Kiyonori
authors.initials: K
authors.lastname: Kai
authors.forename: Munehiro
authors.initials: M
authors.lastname: Teranishi
authors.forename: Wataru
authors.initials: W
authors.lastname: Takasaki
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism* / Q000627:therapeutic use; D019328:Buthionine Sulfoximine / Q000494:pharmacology; D002083:Butylated Hydroxyanisole / Q000627:therapeutic use; D059305:Diet, High-Fat; D005978:Glutathione / Q000096:biosynthesis / Q000378:metabolism* / Q000502:physiology*; D008099:Liver / Q000378:metabolism*; D008297:Male; D047508:Massive Hepatic Necrosis / Q000139:chemically induced* / Q000188:drug therapy; D055432:Metabolomics; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000209:etiology* / Q000378:metabolism*; D018384:Oxidative Stress; D013853:Thioacetamide / Q000633:toxicity*; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism
chemical_list: D000975:Antioxidants; D017392:Thiobarbituric Acid Reactive Substances; D013853:Thioacetamide; D002083:Butylated Hydroxyanisole; D019328:Buthionine Sulfoximine; D005978:Glutathione