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

Hidenori Yamada, Noriyuki Akahoshi, Shotaro Kamata, Yoshifumi Hagiya, Takako Hishiki, Yoshiko Nagahata, Tomomi Matsuura, Naoharu Takano, Masatomo Mori, Yasuki Ishizaki, Takashi Izumi, Yoshito Kumagai, Tadashi Kasahara, Makoto Suematsu, Isao Ishii

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51 Citations (Scopus)

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 2S), 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 2S 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.

Original languageEnglish
Pages (from-to)1716-1726
Number of pages11
JournalFree Radical Biology and Medicine
Volume52
Issue number9
DOIs
Publication statusPublished - 2012 May 1

Keywords

  • Antioxidants
  • Homocysteine
  • Metabolome
  • Methionine sulfoxide
  • Transamination
  • Transsulfuration

ASJC Scopus subject areas

  • Biochemistry
  • Physiology (medical)

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  • Cite this

    Yamada, H., Akahoshi, N., Kamata, S., Hagiya, Y., Hishiki, T., Nagahata, Y., Matsuura, T., Takano, N., Mori, M., Ishizaki, Y., Izumi, T., Kumagai, Y., Kasahara, T., Suematsu, M., & Ishii, I. (2012). Methionine excess in diet induces acute lethal hepatitis in mice lacking cystathionine γ-lyase, an animal model of cystathioninuria. Free Radical Biology and Medicine, 52(9), 1716-1726. https://doi.org/10.1016/j.freeradbiomed.2012.02.033