title: Tryptophan protects hepatocytes against reactive oxygen species-dependent cell death via multiple pathways including Nrf2-dependent gene induction.
abstract: Hepatocyte apoptosis plays a key role in the pathogenesis of immune-mediated hepatitis. However, the detailed mechanisms of apoptosis signaling are still unclear and effective therapeutic drugs for hepatitis have been explored. Here, we show that tryptophan (Trp) suppressed IFN-γ-mediated hepatic apoptosis in vitro. Trp inhibited the downstream apoptotic events of mitochondria disruption, such as cell death and caspase-3 activation, while it did not influence upstream signaling including STAT1 activation and IRF1 expression. Trp suppressed reactive oxygen species (ROS) generation at the mitochondria. IFN-γ induced ROS in mitochondria by inhibiting complex I and III, but not II. This ROS generation by IFN-γ required de novo protein synthesis. Trp showed relatively weak direct scavenging activity but antagonized IFN-γ against the suppression of complex I. In addition, Trp increased the expression of the Nrf2-dependent antioxidant genes NQO1, HO-1 and GCS in hepatocytes both in vitro and in vivo. Finally, the administration of Trp in an acetaminophen-induced ROS-dependent hepatitis model suppressed the liver injury in vivo. Thus, Trp protects hepatocytes from ROS-dependent cell injury via multiple pathways. This study suggests Trp as a therapeutic antioxidant drug for hepatitis and a regulator for Nrf2-dependent genes.
authors.affiliation: Department of Pharmaceutical Sciences, Musashino University, 1-1-20 Shinmachi, Nishi-Tokyo, 202-8585, Japan.
authors.forename: Takuya
authors.initials: T
authors.lastname: Kimura
authors.affiliation: Department of Pharmaceutical Sciences, Musashino University, 1-1-20 Shinmachi, Nishi-Tokyo, 202-8585, Japan. ywatanab@musashino-u.ac.jp.
authors.forename: Yoshifumi
authors.identifier: http://orcid.org/0000-0002-7120-3097
authors.initials: Y
authors.lastname: Watanabe
mesh_terms: D000818:Animals; D017209:Apoptosis; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D016923:Cell Death; D002478:Cells, Cultured; D005260:Female; D022781:Hepatocytes / Q000166:cytology* / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction; D014364:Tryptophan / Q000378:metabolism*
chemical_list: D051267:NF-E2-Related Factor 2; D017382:Reactive Oxygen Species; D014364:Tryptophan; D053148:Caspase 3
keywords: Apoptosis; Hepatocyte; Nrf2; Reactive oxygen species; Tryptophan