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. 2001 Apr 10;98(8):4611-6.
doi: 10.1073/pnas.081082098. Epub 2001 Apr 3.

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

K Chan  1 , X D Han, Y W Kan
Affiliations

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

K Chan et al. Proc Natl Acad Sci U S A. .

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 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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Figures

Figure 1
Figure 1
Survival of Nrf2−/− and wild-type mice injected i.p. with increasing doses of APAP. Percent survival at 48 h is plotted as a function of dose. LD50 values are indicated with arrows. Eight mice were used for each dose.
Figure 2
Figure 2
Individual serum ALT values of mice at 24 h after injection with different doses of APAP. (A) Ten wild-type (WT) and nrf2 knockout (KO) mice were injected with doses of 100, 200, and 300 mg/kg APAP; individual serum ALT values are plotted (P(100) = 0.056, P(200) = 0.102; P(300) was not calculated because two data points were lost when two Nrf2−/− mice died before blood collection). (B) Eight wild-type and nrf2 knockout mice were injected with 1,200 mg/kg NAC (+N) in addition to APAP at 300, 400 or 600, and 800 mg/kg APAP.
Figure 3
Figure 3
Liver GSH content and gene expression after APAP injection. Mice were injected with 100 (open symbols) or 400 mg/kg (closed symbols) APAP and killed after 90, 180, and 270 min. (A) Liver GSH expressed as micromol/gram of liver as a function of time after injection. (B) Gene expression calculated from Northern blots and expressed as a percentage of the level found in liver of untreated wild-type mice after normalization with glyceraldehyde-3-phosphate dehydrogenase.
Figure 4
Figure 4
Nrf2 gene expression after 100 and 400 mg/kg APAP injection.
Figure 5
Figure 5
Liver injury found in mice at 90 min after injection of 400 mg/kg APAP. Moderate injury can be observed by the presence of cytoplasmic vacuoles in centrilobular hepatocytes in the Nrf2−/− livers (hematoxylin/eosin). (×184.)
See this image and copyright information in PMC

References

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