An Important Function of Nrf2 in Combating Oxidative Stress: Detoxification of Acetaminophen

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 gcsHand gcsLas well as gss in the livers of the Nrf2-/-mice. In addition, the expression of ugt1a6 and gstpi 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.