title: Methionine excess in diet induces acute lethal hepatitis in mice lacking cystathionine γ-lyase, an animal model of cystathioninuria.
abstract: Physiological roles of the transsulfuration pathway have been recognized by its contribution to the synthesis of cytoprotective cysteine metabolites, such as glutathione, taurine/hypotaurine, and hydrogen sulfide (H(2)S), whereas its roles in protecting against methionine toxicity remained to be clarified. This study aimed at revealing these roles by analyzing high-methionine diet-fed transsulfuration-defective cystathionine γ-lyase-deficient (Cth(-/-)) mice. Wild-type and Cth(-/-) mice were fed a standard diet (1 × Met: 0.44%) or a high-methionine diet (3 × Met or 6 × Met), and hepatic conditions were monitored by serum biochemistry and histology. Metabolome analysis was performed for methionine derivatives using capillary electrophoresis- or liquid chromatography-mass spectrometry and sulfur-detecting gas chromatography. The 6 × Met-fed Cth(-/-) (not 1 × Met-fed Cth(-/-) or 6 × Met-fed wild type) mice displayed acute hepatitis, which was characterized by markedly elevated levels of serum alanine/aspartate aminotransferases and serum/hepatic lipid peroxidation, inflammatory cell infiltration, and hepatocyte ballooning; thereafter, they died of gastrointestinal bleeding due to coagulation factor deficiency. After 1 week on 6 × Met, blood levels of ammonia/homocysteine and hepatic levels of methanethiol/3-methylthiopropionate (a methionine transamination product/methanethiol precursor) became significantly higher in Cth(-/-) mice than in wild-type mice. Although hepatic levels of methionine sulfoxide became higher in 6 × Met-fed wild-type mice and Cth(-/-) mice, those of glutathione, taurine/hypotaurine, and H(2)S became lower and serum levels of homocysteine became much higher in 6 × Met-fed Cth(-/-) mice than in wild-type mice. Thus, transsulfuration plays a critical role in the detoxification of excessive methionine by circumventing aberrant accumulation of its toxic transamination metabolites, including ammonia, methanethiol, and 3-methylthiopropionate, in addition to synthesizing cysteine-derived antioxidants to counteract accumulated pro-oxidants such as methionine sulfoxide and homocysteine.
authors.affiliation: Department of Biochemistry, School of Medicine, Keio University, Tokyo 160-8582, Japan.
authors.forename: Hidenori
authors.initials: H
authors.lastname: Yamada
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Akahoshi
authors.forename: Shotaro
authors.initials: S
authors.lastname: Kamata
authors.forename: Yoshifumi
authors.initials: Y
authors.lastname: Hagiya
authors.forename: Takako
authors.initials: T
authors.lastname: Hishiki
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Nagahata
authors.forename: Tomomi
authors.initials: T
authors.lastname: Matsuura
authors.forename: Naoharu
authors.initials: N
authors.lastname: Takano
authors.forename: Masatomo
authors.initials: M
authors.lastname: Mori
authors.forename: Yasuki
authors.initials: Y
authors.lastname: Ishizaki
authors.forename: Takashi
authors.initials: T
authors.lastname: Izumi
authors.forename: Yoshito
authors.initials: Y
authors.lastname: Kumagai
authors.forename: Tadashi
authors.initials: T
authors.lastname: Kasahara
authors.forename: Makoto
authors.initials: M
authors.lastname: Suematsu
authors.forename: Isao
authors.initials: I
authors.lastname: Ishii
mesh_terms: D000586:Amination; D000818:Animals; D002478:Cells, Cultured; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology*; D002849:Chromatography, Gas; D002853:Chromatography, Liquid; D003542:Cystathionine gamma-Lyase / Q000235:genetics*; D004032:Diet; D004195:Disease Models, Animal; D019075:Electrophoresis, Capillary; D020138:Hyperhomocysteinemia / Q000235:genetics*; D013058:Mass Spectrometry; D008715:Methionine / Q000008:administration & dosage* / Q000633:toxicity; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010084:Oxidation-Reduction
chemical_list: D008715:Methionine; D003542:Cystathionine gamma-Lyase