title: xCT deficiency aggravates acetaminophen-induced hepatotoxicity under inhibition of the transsulfuration pathway.
abstract: Cystine, an oxidized form of cysteine (Cys), is imported into cells via the protein xCT, which is also associated with the export of glutamate as the counter amino acid. In the current study, we attempted to rationalize roles of xCT in the livers of male mice. While xCT was not expressed in the livers of ordinary mice, it was induced under conditions of glutathione depletion, caused by the administration of acetaminophen (AAP). To differentiate the role between xCT and the transsulfuration pathway on the supply of Cys, we employed an inhibitor of the enzyme cystathionine γ-lyase, propargylglycine (PPG). This inhibitor caused a marked aggravation in AAP-induced hepatic damage and the mortality of the xCT-/-mice was increased to a greater extent than that for the xCT+/+mice. While a PPG pretreatment had no effect on liver condition or Cys levels, the administration of AAP to the PPG-pretreated mice reduced the levels of Cys as well as glutathione to very low levels in both the xCT+/+and xCT-/-mice. These findings indicate that the transsulfuration pathway plays a major role in replenishing Cys when glutathione levels are low. Moreover, an ascorbic acid insufficiency, induced by Akr1a ablation, further aggravated the AAP-induced liver damage in the case of the xCT deficiency, indicating that glutathione and ascorbic acid function cooperatively in protecting the liver. In conclusion, while the transsulfuration pathway plays a primary role in supplying Cys to the redox system in the liver, xCT is induced in cases of emergencies, by compensating for Cys supply systems.
authors.affiliation: a Department of Biochemistry and Molecular Biology , Graduate School of Medical Science, Yamagata University , Yamagata , Japan.|b Department of Animal Biotechnology , Konkuk University , Seoul , Republic of Korea.
authors.forename: Eun Sil
authors.initials: ES
authors.lastname: Kang
authors.affiliation: a Department of Biochemistry and Molecular Biology , Graduate School of Medical Science, Yamagata University , Yamagata , Japan.
authors.forename: Jaeyong
authors.initials: J
authors.lastname: Lee
authors.affiliation: a Department of Biochemistry and Molecular Biology , Graduate School of Medical Science, Yamagata University , Yamagata , Japan.
authors.forename: Takujiro
authors.initials: T
authors.lastname: Homma
authors.affiliation: a Department of Biochemistry and Molecular Biology , Graduate School of Medical Science, Yamagata University , Yamagata , Japan.
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Kurahashi
authors.affiliation: a Department of Biochemistry and Molecular Biology , Graduate School of Medical Science, Yamagata University , Yamagata , Japan.
authors.forename: Sho
authors.initials: S
authors.lastname: Kobayashi
authors.affiliation: c Department of Pathology and Cell Biology , University of Occupational and Environmental Health , Kitakyushu , Japan.
authors.forename: Atsunori
authors.initials: A
authors.lastname: Nabeshima
authors.affiliation: c Department of Pathology and Cell Biology , University of Occupational and Environmental Health , Kitakyushu , Japan.
authors.forename: Sohsuke
authors.initials: S
authors.lastname: Yamada
authors.affiliation: b Department of Animal Biotechnology , Konkuk University , Seoul , Republic of Korea.
authors.forename: Han Geuk
authors.initials: HG
authors.lastname: Seo
authors.affiliation: d Department of Internal Medicine , Osaka Hospital, Japan Community Healthcare Organization , Osaka , Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Miyata
authors.affiliation: e Laboratory of Biochemistry and Molecular Biology, Department of Medical Technology, Faculty of Medicine , Niigata University , Niigata , Japan.
authors.forename: Hideyo
authors.initials: H
authors.lastname: Sato
authors.affiliation: a Department of Biochemistry and Molecular Biology , Graduate School of Medical Science, Yamagata University , Yamagata , Japan.
authors.forename: Junichi
authors.initials: J
authors.lastname: Fujii
mesh_terms: D000082:Acetaminophen / Q000633:toxicity*; D027182:Amino Acid Transport System y+ / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000235:genetics / Q000378:metabolism*; D003545:Cysteine / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015398:Signal Transduction
chemical_list: D027182:Amino Acid Transport System y+; C492255:Slc7a11 protein, mouse; D000082:Acetaminophen; D005978:Glutathione; D003545:Cysteine
keywords: Acetaminophen; amino acid transporter; cysteine; glutathione