title: Oxidative stress caused by a SOD1 deficiency ameliorates thioacetamide-triggered cell death via CYP2E1 inhibition but stimulates liver steatosis.
abstract: We investigated the responses of mice that are defective in the superoxide-scavenging enzyme SOD1 to thioacetamide (TAA)-induced hepatotoxicity. When a lethal dose of TAA (500 mg/kg) was intraperitoneally injected, the wild-type (WT) mice all died within 36 h, but all of the SOD1-knockout (KO) mice survived. Treatment with an SOD1 inhibitor rendered the WT mice resistant to TAA toxicity. To elucidate the mechanism responsible for this, we examined the acute effects of a sublethal dose of TAA (200 mg/kg) on the livers of WT and KO mice. The extent of TAA-induced liver damage was less in the KO mice, but, instead, lipogenesis was further advanced in the SOD1-KO livers. The levels of proteins modified with acetyllysine, a marker for TAA-mediated injury, were lower in the KO mice than the WT mice upon the TAA treatment. The KO mice, which were under oxidative stress per se, exhibited a lower CYP2E1 activity, and this appeared to result in a decrease in the production of reactive oxygen species (ROS) during TAA metabolism. Both cleaved ATF6, a transcriptional regulator that is activated by endoplasmic reticulum (ER) stress, and CHOP, a death signal mediator, were highly elevated in the WT mice as the result of the TAA treatment and consistent with the liver damage. We conclude that elevated TAA metabolites and reactive oxygen species that are produced by CYP-mediated drug metabolism trigger lipogenesis as well as liver damage via ER stress and determine the fate of the mice.
authors.affiliation: Department of Biochemistry and Molecular Biology, Graduate School of Medical Science, Yamagata University, 2-2-2 Iidanishi, Yamagata, 990-9585, Japan.
authors.forename: Takaya
authors.initials: T
authors.lastname: Shirato
authors.affiliation: Department of Biochemistry and Molecular Biology, Graduate School of Medical Science, Yamagata University, 2-2-2 Iidanishi, Yamagata, 990-9585, Japan.
authors.forename: Takujiro
authors.initials: T
authors.lastname: Homma
authors.affiliation: Department of Biochemistry and Molecular Biology, Graduate School of Medical Science, Yamagata University, 2-2-2 Iidanishi, Yamagata, 990-9585, Japan.
authors.forename: Jaeyong
authors.initials: J
authors.lastname: Lee
authors.affiliation: Department of Biochemistry and Molecular Biology, Graduate School of Medical Science, Yamagata University, 2-2-2 Iidanishi, Yamagata, 990-9585, Japan.|Department of Pathology and Cell Regulation, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan.
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Kurahashi
authors.affiliation: Department of Biochemistry and Molecular Biology, Graduate School of Medical Science, Yamagata University, 2-2-2 Iidanishi, Yamagata, 990-9585, Japan. jfujii@med.id.yamagata-u.ac.jp.
authors.forename: Junichi
authors.identifier: http://orcid.org/0000-0003-2267-7357
authors.initials: J
authors.lastname: Fujii
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects* / Q000235:genetics; D019392:Cytochrome P-450 CYP2E1 / Q000235:genetics / Q000378:metabolism*; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects / Q000502:physiology; D004798:Enzymes / Q000378:metabolism; D005234:Fatty Liver / Q000139:chemically induced* / Q000473:pathology; D008658:Inactivation, Metabolic / Q000187:drug effects; D050356:Lipid Metabolism / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018384:Oxidative Stress / Q000187:drug effects / Q000235:genetics; D000072105:Superoxide Dismutase-1 / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D013853:Thioacetamide / Q000008:administration & dosage / Q000633:toxicity*
chemical_list: D000975:Antioxidants; D004798:Enzymes; D013853:Thioacetamide; D019392:Cytochrome P-450 CYP2E1; C000606291:Sod1 protein, mouse; D000072105:Superoxide Dismutase-1
keywords: CYP; ER stress; Oxidative stress; Steatosis; Superoxide; Thioacetamide