Host: The Japanese Society of Toxicology
Name : The 47th Annual Meeting of the Japanese Society of Toxicology
Date : 2020 -
Keap1-Nrf2 system is a cytoprotective mechanism that defends against a variety of toxicants and oxidative stress. We have been examined the relationship of Keap1-Nrf2 system and detoxication in the liver using genetically modified animals. Overdose of acetaminophen (APAP), an antipyretic analgesic, leads to severer liver injury in Nrf2 knockout mice in which Nrf2-target gene products responsible for detoxication and antioxidant are downregulated. On the other hands, more than half of Nrf2 knockout mice have a congenital portosystemic shunt and suppresses APAP-induced hepatotoxicity. Unlike acetaminophen that leads to necrosis around central veins, a heme synthesis inhibitor DDC is a hepatotoxicant that causes cholangiocytes expansion around portal veins. Liver-specific Keap1 knockout mice in which Nrf2 constitutively actives significantly ameliorated DDC-induced hepatotoxicity. In addition, Nrf2 activation protects liver cancers caused by aflatoxin B1 (AFB1) that is produced by molds contaminated in foods. However, this experimental model is not suitable for mice. Therefore, we generated Nrf2 knockout rat and dosed AFB1 to the rats. We hypothesized that Nrf2 knockout rats are susceptible to liver cancers with severer DNA damage. However, Nrf2 knockout rats died of not cancers but cirrhosis with fibrosis and hepatocyte regeneration. Interestingly, Keap1 knockout rats with constitutive Nrf2 activation died at perinatal period with jaundice, lacking of intrahepatic bile ducts around portal veins. Analyses using these animal models demonstrate that Nrf2 is the master transcription factor responsible for not only detoxication but also tissue formations of the shunt and intrahepatic bile ducts at developing stage.
