Methionine excess in diet induces acute lethal hepatitis in mice lacking cystathionine γ-lyase, an animal model of cystathioninuria

• Published in: Free radical biology & medicine Vol. 52; no. 9; pp. 1716 - 1726
• Main Authors: Yamada, Hidenori, Akahoshi, Noriyuki, Kamata, Shotaro, Hagiya, Yoshifumi, Hishiki, Takako, Nagahata, Yoshiko, Matsuura, Tomomi, Takano, Naoharu, Mori, Masatomo, Ishizaki, Yasuki, Izumi, Takashi, Kumagai, Yoshito, Kasahara, Tadashi, Suematsu, Makoto, Ishii, Isao
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.05.2012
• Subjects: Alanine; Amination; Ammonia; Animal models; Animals; Antioxidants; Aspartate aminotransferase; aspartate transaminase; Bleeding; Blood levels; blood serum; capillary electrophoresis; Cells, Cultured; Chemical and Drug Induced Liver Injury - etiology; Chromatography, Gas; Chromatography, Liquid; coagulation; Coagulation factors; cystathionine; Cystathionine gamma -lyase; Cystathionine gamma-Lyase - genetics; Cystathioninuria; Cysteine; Detoxification; Diet; Diets; Disease Models, Animal; Electrophoresis, Capillary; Gas chromatography; gastrointestinal system; Glutathione; hemorrhage; Hepatitis; Hepatocytes; histology; Homocysteine; Hydrogen sulfide; Hyperhomocysteinemia - genetics; Inflammation; Lipid peroxidation; liquid chromatography; Liver; Mass Spectrometry; Metabolites; Metabolome; metabolomics; Methanethiol; Methionine; Methionine - administration & dosage; Methionine - toxicity; Methionine sulfoxide; Mice; Mice, Inbred C57BL; Mice, Knockout; Oxidation-Reduction; Serum levels; Spectrometry; Stem cells; Taurine; Toxicity; Transamination; Transsulfuration; MAT; PT; ALP; Methionine sulfoxide; MTP; ALT; Transamination; Ac-Met sulfoxide; CE–MS; Antioxidants; LDH; TUNEL; CBS; BUN; GSH; DIC; GSSG; AST; CK; Metabolome; TBARS; APTT; KMTB; CTH; LC; ROS; SAH; Homocysteine; Transsulfuration; SAM
• ISSN: 0891-5849; 1873-4596
• DOI: 10.1016/j.freeradbiomed.2012.02.033

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 (H2S), 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 1week 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 H2S 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. [Display omitted] ► Transsulfuration-defective Cth−/− mice displayed hepatitis upon excessive Met intake. ► Metabolome analysis revealed accumulation of Met oxidation/transamination products. ► Metabolome analysis revealed deficiency of Cys-derived antioxidants, GSH and taurine. ► Transsulfuration was found to be essential for effective clearance of overloaded Met.