Hemizygosity of transsulfuration genes confers increased vulnerability against acetaminophen-induced hepatotoxicity in mice

Yoshifumi Hagiya, Shotaro Kamata, Saya Mitsuoka, Norihiko Okada, Saori Yoshida, Junya Yamamoto, Rika Ohkubo, Yumi Abiko, Hidenori Yamada, Noriyuki Akahoshi, Tadashi Kasahara, Yoshito Kumagai, Isao Ishii

研究成果: Article

19 引用 (Scopus)

抜粋

The key mechanism for acetaminophen hepatotoxicity is cytochrome P450 (CYP)-dependent formation of N-acetyl-p-benzoquinone imine, a potent electrophile that forms protein adducts. Previous studies revealed the fundamental role of glutathione, which binds to and detoxifies N-acetyl-p-benzoquinone imine. Glutathione is synthesized from cysteine in the liver, and N-acetylcysteine is used as a sole antidote for acetaminophen poisoning. Here, we evaluated the potential roles of transsulfuration enzymes essential for cysteine biosynthesis, cystathionine β-synthase (CBS) and cystathionine γ-lyase (CTH), in acetaminophen hepatotoxicity using hemizygous (Cbs+/- or Cth+/-) and homozygous (Cth-/-) knockout mice. At 4h after intraperitoneal acetaminophen injection, serum alanine aminotransferase levels were highly elevated in Cth-/- mice at 150mg/kg dose, and also in Cbs+/- or Cth+/- mice at 250mg/kg dose, which was associated with characteristic centrilobular hepatocyte oncosis. Hepatic glutathione was depleted while serum malondialdehyde accumulated in acetaminophen-injected Cth-/- mice but not wild-type mice, although glutamate-cysteine ligase (composed of catalytic [GCLC] and modifier [GCLM] subunits) became more activated in the livers of Cth-/- mice with lower Km values for Cys and Glu. Proteome analysis using fluorescent two-dimensional difference gel electrophoresis revealed 47 differentially expressed proteins after injection of 150mgacetaminophen/kg into Cth-/- mice; the profiles were similar to 1000mgacetaminophen/kg-treated wild-type mice. The prevalence of Cbs or Cth hemizygosity is estimated to be 1:200-300 population; therefore, the deletion or polymorphism of either transsulfuration gene may underlie idiosyncratic acetaminophen vulnerability along with the differences in Cyp, Gclc, and Gclm gene activities.

元の言語English
ページ(範囲)195-206
ページ数12
ジャーナルToxicology and Applied Pharmacology
282
発行部数2
DOI
出版物ステータスPublished - 2015 1 5

ASJC Scopus subject areas

  • Toxicology
  • Pharmacology

フィンガープリント Hemizygosity of transsulfuration genes confers increased vulnerability against acetaminophen-induced hepatotoxicity in mice' の研究トピックを掘り下げます。これらはともに一意のフィンガープリントを構成します。

  • これを引用

    Hagiya, Y., Kamata, S., Mitsuoka, S., Okada, N., Yoshida, S., Yamamoto, J., Ohkubo, R., Abiko, Y., Yamada, H., Akahoshi, N., Kasahara, T., Kumagai, Y., & Ishii, I. (2015). Hemizygosity of transsulfuration genes confers increased vulnerability against acetaminophen-induced hepatotoxicity in mice. Toxicology and Applied Pharmacology, 282(2), 195-206. https://doi.org/10.1016/j.taap.2014.11.015