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 gcs(H) and gcs(L) as 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.
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Cardiovascular Research Institute, Department of Laboratory Medicine and Howard Hughes Medical Institute, University of California, San Francisco, CA 94143-0793, USA.
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D000082:Acetaminophen / Q000493:pharmacokinetics*; D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001483:Base Sequence; D017931:DNA Primers; D004268:DNA-Binding Proteins / Q000502:physiology*; D005260:Female; D020869:Gene Expression Profiling; D005978:Glutathione / Q000097:blood; D008658:Inactivation, Metabolic / Q000502:physiology*; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D051267:NF-E2-Related Factor 2; D018384:Oxidative Stress; D016019:Survival Analysis; D015534:Trans-Activators / Q000502:physiology*
D017931:DNA Primers; D004268:DNA-Binding Proteins; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D015534:Trans-Activators; D000082:Acetaminophen; D000410:Alanine Transaminase; D005978:Glutathione