Nrf2 and antioxidant defense against CYP2E1 toxicity
- PMID: 19671018
- DOI: 10.1517/17425250903143769
Nrf2 and antioxidant defense against CYP2E1 toxicity
Abstract
The transcription factor Nrf2 regulates the expression of important cytoprotective enzymes. Induction of CYP2E1 is one of the central pathways by which ethanol generates oxidative stress. CYP2E1 can be induced by ethanol and several low molecular mass chemicals such as pyrazole. This review discusses biochemical and toxicological effects of CYP2E1 and the effects of Nrf2 in modulating these actions of CYP2E1. Besides ethanol, CYP2E1 metabolizes and activates many other toxicologic important compounds. One approach to try to understand the basic effects and actions of CYP2E1 was to establish HepG2 cell lines that constitutively express human CYP2E1. Ethanol, polyunsaturated fatty acids and iron were toxic to the HepG2 cells, which express CYP2E1 (E47 cells) but not control C34HepG2 cells, which do not express CYP2E1. Toxicity was associated with enhanced oxidant stress and could be prevented by antioxidants and potentiated if glutathione was removed. The E47 cells had higher glutathione levels and a twofold increase in catalase, cytosolic and microsomal glutathione transferase, and heme oxygenase-1 than control HepG2 cells due to activation of their respective genes. These activations were prevented by antioxidants, suggesting that reactive oxygen species generated by CYP2E1 were responsible for the upregulation of these antioxidant genes. This upregulation may reflect an adaptive mechanism to remove CYP2E1-derived oxidants. Increases in Nrf2 protein and mRNA were observed in livers of chronic alcohol-fed mice or rats and of pyrzole-treated rats or mice, conditions known to elevate CYP2E1. E47 cells showed increased Nrf2 mRNA and protein expression compared with control HepG2 C34 cells. Upregulation of antioxidant genes in E47 cells is dependent on Nrf2 and is prevented by siRNA-Nrf2. Blocking Nrf2 by siRNA-Nrf2 decreases glutathione and increases reactive oxygen species and lipid peroxidation, resulting in decreased mitochondrial membrane potential and loss of cell viability of E47 cells, but not C34 cells. Nrf2 is activated and levels of Nrf2 protein and mRNA are increased when CYP2E1 is elevated. These results suggest that Nrf2 plays a key role in the adaptive response against increased oxidative stress caused by CYP2E1 in the HepG2 cells. However, it is not clear whether Nrf2 is protective against CYP2E1 toxicity in vivo as pyrazole which elevates CYP2E1 in wild-type mice did not elevate CYP2E1 in Nrf2 knockout mice, although pyrazole produced toxicity in the Nrf2 knockout mice.
Similar articles
-
Nrf2 and antioxidant defense against CYP2E1 toxicity.Subcell Biochem. 2013;67:105-30. doi: 10.1007/978-94-007-5881-0_2. Subcell Biochem. 2013. PMID: 23400918 Review.
-
Cytochrome P450 2E1-dependent oxidant stress and upregulation of anti-oxidant defense in liver cells.J Gastroenterol Hepatol. 2006 Oct;21 Suppl 3:S22-5. doi: 10.1111/j.1440-1746.2006.04595.x. J Gastroenterol Hepatol. 2006. PMID: 16958665 Review.
-
Oxidative stress mediated toxicity exerted by ethanol-inducible CYP2E1.Toxicol Appl Pharmacol. 2005 Sep 1;207(2 Suppl):70-6. doi: 10.1016/j.taap.2005.01.057. Toxicol Appl Pharmacol. 2005. PMID: 16019049 Review.
-
Nrf2 is increased by CYP2E1 in rodent liver and HepG2 cells and protects against oxidative stress caused by CYP2E1.Hepatology. 2006 Jan;43(1):144-53. doi: 10.1002/hep.21004. Hepatology. 2006. PMID: 16374848
-
Opposite action of S-adenosyl methionine and its metabolites on CYP2E1-mediated toxicity in pyrazole-induced rat hepatocytes and HepG2 E47 cells.Am J Physiol Gastrointest Liver Physiol. 2006 Apr;290(4):G674-84. doi: 10.1152/ajpgi.00406.2005. Epub 2005 Nov 23. Am J Physiol Gastrointest Liver Physiol. 2006. PMID: 16306132
Cited by
-
Influence of Different Plant Extracts on CYP-Mediated Skatole and Indole Degradation in Pigs.Animals (Basel). 2024 Mar 13;14(6):888. doi: 10.3390/ani14060888. Animals (Basel). 2024. PMID: 38539986 Free PMC article.
-
NRF2 Activation by Nitrogen Heterocycles: A Review.Molecules. 2023 Mar 18;28(6):2751. doi: 10.3390/molecules28062751. Molecules. 2023. PMID: 36985723 Free PMC article. Review.
-
PPARα agonist WY-14,643 induces adipose atrophy and fails to blunt chronic ethanol-induced hepatic fat accumulation in mice lacking adipose FGFR1.Biochem Pharmacol. 2021 Oct;192:114678. doi: 10.1016/j.bcp.2021.114678. Epub 2021 Jul 13. Biochem Pharmacol. 2021. PMID: 34265279 Free PMC article.
-
Alcoholic Hepatitis: Lost in Translation.J Clin Transl Hepatol. 2018 Mar 28;6(1):89-96. doi: 10.14218/JCTH.2017.00054. Epub 2017 Dec 17. J Clin Transl Hepatol. 2018. PMID: 29577035 Free PMC article. Review.
-
Alcoholic fatty liver is enhanced in CYP2A5 knockout mice: The role of the PPARα-FGF21 axis.Toxicology. 2017 Mar 15;379:12-21. doi: 10.1016/j.tox.2017.01.016. Epub 2017 Jan 25. Toxicology. 2017. PMID: 28131861 Free PMC article.
Publication types
MeSH terms
Substances
Grants and funding
LinkOut - more resources
Full Text Sources