Activation of nuclear factor E2‐related factor 2 in hereditary tyrosinemia type 1 and its role in survival and tumor development

In tyrosinemia type 1 (HT1), accumulation of toxic metabolites results in oxidative stress and DNA damage, leading to a high incidence of hepatocellular carcinomas. Nuclear factor erythroid‐2 related factor 2 (Nrf2) is a key transcription factor important for cellular protection against oxidative stress and chemical induced liver damage. To specifically address the role of Nrf2 in HT1, fumarylacetoacetate hydrolase ( Fah)/Nrf2 −/− mice were generated. In acute HT1, loss of Nrf2 elicited a strong inflammatory response and dramatically increased the mortality of mice. Following low grade injury, Fah/Nrf2 −/− mice develop a more severe hepatitis and liver fibrosis. The glutathione and cellular detoxification system was significantly impaired in Fah/Nrf2 −/− mice, resulting in increased oxidative stress and DNA damage. Consequently, tumor development was significantly accelerated by loss of Nrf2. Potent pharmacological inducers of Nrf2 such as the triterpenoid analogs 1[2‐cyano‐3,12‐dioxooleana‐1,9(11)‐dien‐28‐oyl]imidazole have been developed as cancer chemoprevention agents. Pretreatment with 1[2‐cyano‐3,12‐dioxooleana‐1,9(11)‐dien‐28‐oyl]imidazole dramatically protected Fah −/− mice against fumarylacetoacetate (Faa)‐induced toxicity. Our data establish a central role for Nrf2 in the protection against Faa‐induced liver injury; the Nrf2 regulated cellular defense not only prevents acute Faa‐induced liver failure but also delays hepatocarcinogenesis in HT1. (H EPATOLOGY 2008;48:487–496.)