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
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...
January 15, 2015: Toxicology and Applied Pharmacology