An important function of Nrf2 in combating oxidative stress: Detoxification of acetaminophen

Abstract

Nrf2, a member of the “cap ‘n collar” group of transcription factors, is important for protecting cells against oxidative damage. We investigated its role in the detoxification of acetaminophen [ N -acetyl- p -aminophenol (APAP)]-induced hepatotoxicity. When Nrf2 knockout (Nrf2 −/− ) and wild-type mice were given APAP by i.p. injection, the Nrf2 −/− mice were highly susceptible to APAP treatment. With doses of APAP that were tolerated by wild-type mice, the Nrf2 −/− mice died of liver failure. When hepatic glutathione was depleted after a dose of 400 mg/kg of APAP, the wild-type mice were able to compensate and regain the normal glutathione level. In contrast, the glutathione level in the Nrf2 −/− mice was not compensated and remained low. This was because of the decrease in the gene expression of gcs H and gcs L as well as gss in the livers of the Nrf2 −/− mice. In addition, the expression of ugt 1a6 and gst pi that detoxify APAP by conjugation was also decreased. This increased susceptibility of the Nrf2 −/− mice to APAP, because of an impaired capacity to replenish their glutathione stores, compounded with a decreased detoxification capability, highlights the importance of Nrf2 in the regulation of glutathione synthesis and cellular detoxification processes.