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

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• 作者：Hidenori Yamada^a ; ^b ; Noriyuki Akahoshi^a ; ^b ; ^c ; Shotaro Kamata^d ; Yoshifumi Hagiya^d ; Takako Hishiki^a ; Yoshiko Nagahata^c ; Tomomi Matsuura^c ; Naoharu Takano^c ; Masatomo Mori^b ; Yasuki Ishizaki^b ; Takashi Izumi^b ; Yoshito Kumagai^e ; Tadashi Kasahara^d ; Makoto Suematsu^a ; ^c ; Isao Ishii^a ; ^b ; ^d ; ^{isao-ishii@umin.ac.jp}
• 关键词：Ac-Met sulfoxide ; N-伪-acetyl-l-methionine sulfoxide ; ALP ; alkaline phosphatase ; ALT ; alanine aminotransferase ; APTT ; activated partial thromboplastin time ; AST ; aspartate aminotransferase ; BUN ; blood urea nitrogen ; CE&ndash ; MS ; capillary electrophoresis&
• 刊名：Free Radical Biology and Medicine
• 出版年：2012
• 期刊代码：105_08915849
• 类别：med
• 出版时间：1 May, 2012
• 卷：52
• 期：9
• 页码：1716-1726
• 文件大小：2514 K

摘要

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 纬-lyase-deficient (Cth^{鈭?鈭?/sup>) mice. Wild-type and Cth鈭?鈭?/sup> mice were fed a standard diet (1 脳 Met: 0.44%) or a high-methionine diet (3 脳 Met or 6 脳 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 脳 Met-fed Cth鈭?鈭?/sup> (not 1 脳 Met-fed Cth鈭?鈭?/sup> or 6 脳 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 脳 Met, blood levels of ammonia/homocysteine and hepatic levels of methanethiol/3-methylthiopropionate (a methionine transamination product/methanethiol precursor) became significantly higher in Cth鈭?鈭?/sup> mice than in wild-type mice. Although hepatic levels of methionine sulfoxide became higher in 6 脳 Met-fed wild-type mice and Cth鈭?鈭?/sup> mice, those of glutathione, taurine/hypotaurine, and H₂S became lower and serum levels of homocysteine became much higher in 6 脳 Met-fed Cth鈭?鈭?/sup> 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.}