Ascorbic acid prevents acetaminophen-induced hepatotoxicity in mice by ameliorating glutathione recovery and autophagy.
Aldehyde reductase (AKR1A) plays a role in the biosynthesis of ascorbic acid (AsA), and AKR1A-deficient mice produce about 10-15% of the AsA that is produced by wild-type mice. We found that acetaminophen (AAP) hepatotoxicity was aggravated in AKR1A-deficient mice. The pre-administration of AsA in the drinking water markedly ameliorated the AAP hepatotoxicity in the AKR1A-deficient mice. Treatment of the mice with AAP decreased both glutathione and AsA levels in the liver in the early phase after AAP administration, and an AsA deficiency delayed the recovery of the glutathione content in the healing phase. While in cysteine supply systems; a neutral amino acid transporter ASCT1, a cystine transporter xCT, enzymes for the transsulfuration pathway, and autophagy markers, were all elevated in the liver as the result of the AAP treatment, the AsA deficiency suppressed their induction. Thus, AsA appeared to exert a protective effect against AAP hepatotoxicity by ameliorating the supply of cysteine that is available for glutathione synthesis as a whole. Because some drugs produce reactive oxygen species, resulting in the consumption of glutathione during the metabolic process, the intake of sufficient amounts of AsA would be beneficial for protecting against the hepatic damage caused by such drugs.
Department of Biochemistry and Molecular Biology, Graduate School of Medical Science, Yamagata University, Yamagata 990-9585, Japan.
Toshihiro
T
Kurahashi
Department of Biochemistry and Molecular Biology, Graduate School of Medical Science, Yamagata University, Yamagata 990-9585, Japan.
Jaeyong
J
Lee
Department of Pathology and Cell Biology, University of Occupational and Environmental Health, Kitakyushu, Fukuoka 807-8555, Japan.
Atsunori
A
Nabeshima
Department of Biochemistry and Molecular Biology, Graduate School of Medical Science, Yamagata University, Yamagata 990-9585, Japan.
Takujiro
T
Homma
Department of Biochemistry and Molecular Biology, Graduate School of Medical Science, Yamagata University, Yamagata 990-9585, Japan.
Eun Sil
ES
Kang
Department of Biochemistry and Molecular Biology, Graduate School of Medical Science, Yamagata University, Yamagata 990-9585, Japan.
Yuka
Y
Saito
Department of Pathology and Cell Biology, University of Occupational and Environmental Health, Kitakyushu, Fukuoka 807-8555, Japan.
Sohsuke
S
Yamada
Department of Pathology and Cell Biology, University of Occupational and Environmental Health, Kitakyushu, Fukuoka 807-8555, Japan.
Toshiyuki
T
Nakayama
Department of Bio-functional Science, Faculty of Pharmacological Science, Kyushu University, Fukuoka 812-8582, Japan; JST, PRESTO, 4-1-8 Honcho, Kawaguchi, Saitama 332-0012, Japan.
Ken-Ichi
K
Yamada
Department of Internal Medicine, Osaka Hospital, Japan Community Healthcare Organization, Osaka 553-0003, Japan.
Satoshi
S
Miyata
Department of Biochemistry and Molecular Biology, Graduate School of Medical Science, Yamagata University, Yamagata 990-9585, Japan. Electronic address: jfujii@med.id.yamagata-u.ac.jp.
Junichi
J
Fujii
D000082:Acetaminophen / Q000633:toxicity*; D000449:Aldehyde Reductase / Q000378:metabolism; D000818:Animals; D001205:Ascorbic Acid / Q000737:chemistry*; D001343:Autophagy; D003433:Crosses, Genetic; D003545:Cysteine / Q000737:chemistry; D005838:Genotype; D005978:Glutathione / Q000378:metabolism*; D006168:Guinea Pigs; D022781:Hepatocytes / Q000378:metabolism; D007150:Immunohistochemistry; D015227:Lipid Peroxidation; D008099:Liver / Q000187:drug effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017382:Reactive Oxygen Species / Q000378:metabolism
D017382:Reactive Oxygen Species; D000082:Acetaminophen; D000449:Aldehyde Reductase; D005978:Glutathione; D003545:Cysteine; D001205:Ascorbic Acid
Acetaminophen; Amino acid transporter; Ascorbic acid; Autophagy; Glutathione