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Oxidative stress and redox imbalance in acetaminophen toxicity

The Pharmacogenomics Journal volume 1, pages 165–166 (2001)Cite this article

Acetaminophen [N-acetyl-p-amino phenol (APAP)] is one of the most widely used analgesic drugs worldwide. It is a major cause of liver failure and causes death when taken in excess. Therefore, elucidation of the mechanism of acetaminophen toxicity is an important matter for medical and pharmaceutical research. Although the precise mechanism is still unknown, oxidative damage and redox imbalance have been suggested as the mechanism of acetaminophen toxicity.

Chan et al clearly demonstrated the importance of Nrf2 in the detoxification of acetaminophen in their recent paper entitled ‘An important function of Nrf2 in combating oxidative stress: detoxification of acetaminophen’.1 They showed that the toxicity of acetaminophen is markedly augmented in Nrf2 knock out mice. The most striking data are that the Nrf2 knock out mice died rapidly between 6 and 12 h after injection, whereas the wild-type mice died over a more extended period, with the last deaths occurring between 36 and 48 h post injection. The LD50 was 235 and 320 mg kg−1 for male and female Nrf2 knock out mice, respectively, and 400 and 540 mg kg−1 for the male and female wild-type mice, respectively. Nrf2 is a member of the Cap‘n'Collar/basic leucine zipper (CNC-bZIP) family of transcription factors including NF-E2p45, Nrf1, Nrf2,2,3,4 Bachl, and Bach2. Nrf2 forms heterodimers with small Maf proteins, binding to the antioxidant respon- sive element (ARE).5 The optimal recognition sequence of v-Maf and NF-E2p45 is similar to the ARE/electrophile-responsive element (EpRE)6 which is identified as an element to respond to electrophile targeting xenobiotics. Nrf2 is reported to regulate genes such as the human and rat NAD(P)H: quinone oxidoreductase genes, the rat and murine glutathione S-transferase Ya genes and the human γ-glutamylcysteine synthetase (GCS) subunit genes.7,8 Indeed, they revealed the decrease in gene expression of γ-glutamylcysteine synthetase, the rate-limiting enzyme in the synthetic pathway of glutathione, and glutathione S-transferease in the liver of Nrf2 knock out mice. In addition, they showed that expression of detoxifying enzymes such as glutathione S-transferase pi (GSTpi) and UDP-glucuronosyltransferase (UGT) was significantly lower in Nrf2 knock out mice, indicating the contribution of the conjugation process. Hence, this study and these accumulating works strongly support the idea that Nrf2 is a regulator of the phase II enzyme genes.

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References

  1. Chan K et al. Proc Natl Acad Sci USA 2001 98: 4611–4616

  2. Chui DH et al. Biochem Biophys Res Commun 1995 209: 40–46

  3. Itoh K et al. Mol Cell Biol 1995 15: 4184–4193

  4. Moi P et al. Proc Natl Acad Sci USA 1994 91: 9926–9930

  5. Rushmore TH et al. J Biol Chem 1991 266: 11632–11639

  6. Friling RS et al. Proc Natl Acad Sci USA 1990 87: 6258–6262

  7. Itoh K et al. Biochem Biophys Res Commun 1997 236: 313–322

  8. Wild AC et al. J Biol Chem 1999 274: 33627–33636

  9. Ishii T et al. J Biol Chem 2000 275: 16023–16029

  10. Holmgren A, Björnstedt M . Meth Enzymol 1995 252: 199–208

  11. Kim Y-C et al. J Biol Chem 2001 276: 18399–18406

  12. Ueda S et al. J Immunol 1998 161: 6689–6695

  13. Itoh K et al. Genes Dev 1999 13: 76–86

  14. Yu R et al. J Biol Chem 2000 275: 9612–9619

  15. Huang H-C et al. Proc Natl Acad Sci USA 2000 97: 12475–12480

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  1. Institute for Virus Research, Kyoto University, Kawahara-cho, Sakyo, Kyoto, Japan

    H Masutani

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Masutani, H. Oxidative stress and redox imbalance in acetaminophen toxicity. Pharmacogenomics J 1, 165–166 (2001). https://doi.org/10.1038/sj.tpj.6500036

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