title: Inhibition of glutathione production by L-S,R-buthionine sulfoximine activates hepatic ascorbate synthesis - A unique anti-oxidative stress mechanism in mice.
abstract: Glutathione (GSH) and ascorbate, the cytoplasmic antioxidants, can regenerate and replace each other in scavenging reactive oxygen species reaction. Mice, but not guinea pigs, produce ascorbate endogenously. l-Buthionine-S,R-sulfoximine (L-S,R-BSO) substantially inhibited GSH production at a greater degree and caused a higher toxicity to guinea pigs than mice, implying that mice may have an additional protective mechanism against oxidative stress injury. Indeed, administration of L-S,R-BSO to mice inhibited tissue GSH production while increasing ascorbate levels. L-S,R-BSO also increased tissue ascorbate levels in mice fed a ascorbate and dehydroascorbate-free diet suggesting activation of ascorbate synthesis, which was further confirmed by increased urinary ascorbate excretion. Other reagents inhibiting GSH production also increased tissue ascorbate levels. The results of Northern blot and promoter assay showed that L-S,R-BSO increased mRNA expression and promoter activity of mouse liver L-gulono-γ-lactone oxidase, the critical enzyme for ascorbate synthesis. Taken together, our study demonstrates that inhibition of GSH production activates ascorbate synthesis to protect mice against oxidative stress injury, the mechanism which is not present in guinea pigs or humans.
authors.affiliation: College of Life Sciences, Key Laboratory of Bioactive Materials of Ministry of Education, Nankai University, Tianjin, China.
authors.forename: Miao
authors.initials: M
authors.lastname: Yu
authors.affiliation: College of Life Sciences, Key Laboratory of Bioactive Materials of Ministry of Education, Nankai University, Tianjin, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Liu
authors.affiliation: College of Biomedical Engineering, Hefei University of Technology, Hefei, China; College of Life Sciences, State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin, China.
authors.forename: Yajun
authors.initials: Y
authors.lastname: Duan
authors.affiliation: College of Biomedical Engineering, Hefei University of Technology, Hefei, China; School of Medicine, Nankai University, Tianjin, China.
authors.forename: Yuanli
authors.initials: Y
authors.lastname: Chen
authors.affiliation: College of Biomedical Engineering, Hefei University of Technology, Hefei, China; College of Life Sciences, State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin, China.
authors.forename: Jihong
authors.initials: J
authors.lastname: Han
authors.affiliation: College of Life Sciences, Key Laboratory of Bioactive Materials of Ministry of Education, Nankai University, Tianjin, China. Electronic address: sunlei0911159@163.com.
authors.forename: Lei
authors.initials: L
authors.lastname: Sun
authors.affiliation: College of Biomedical Engineering, Hefei University of Technology, Hefei, China; College of Life Sciences, State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin, China. Electronic address: yang2013@qq.com.
authors.forename: Xiaoxiao
authors.initials: X
authors.lastname: Yang
mesh_terms: D000818:Animals; D001205:Ascorbic Acid / Q000096:biosynthesis*; D019328:Buthionine Sulfoximine / Q000494:pharmacology*; D005978:Glutathione / Q000096:biosynthesis*; D006168:Guinea Pigs; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D018384:Oxidative Stress / Q000187:drug effects*
chemical_list: D019328:Buthionine Sulfoximine; D005978:Glutathione; D001205:Ascorbic Acid
keywords: Ascorbate; GSH; Guinea pig; L-gulono-γ-lactone oxidase; Mouse; Oxidative stress