| First Author | Yamada H | Year | 2012 |
| Journal | Free Radic Biol Med | Volume | 52 |
| Issue | 9 | Pages | 1716-26 |
| PubMed ID | 22387178 | Mgi Jnum | J:183247 |
| Mgi Id | MGI:5318130 | Doi | 10.1016/j.freeradbiomed.2012.02.033 |
| Citation | Yamada H, et al. (2012) Methionine excess in diet induces acute lethal hepatitis in mice lacking cystathionine gamma-lyase, an animal model of cystathioninuria. Free Radic Biol Med 52(9):1716-26 |
| abstractText | 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 gamma-lyase-deficient (Cth(-/-)) mice. Wild-type and Cth(-/-) mice were fed a standard diet (1 x Met: 0.44%) or a high-methionine diet (3 x Met or 6 x 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 x Met-fed Cth(-/-) (not 1 x Met-fed Cth(-/-) or 6 x 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 x 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 x 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 x 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. |
