Tags

Type your tag names separated by a space and hit enter

Pyrazole induced oxidative liver injury independent of CYP2E1/2A5 induction due to Nrf2 deficiency.
Toxicology. 2008 Oct 30; 252(1-3):9-16.T

Abstract

Pyrazole can induce CYP2E1 and 2A5, which produce reactive oxygen species (ROS). Nuclear factor erythroid 2-related factor 2 (Nrf2) regulates important antioxidant enzymes to remove ROS. In this study, we applied Nrf2 knockout mice to test the hypothesis that pyrazole will cause hepatotoxicity and elevate oxidative stress to a greater extent in Nrf2 knockout mice compared to wild type mice. Pyrazole induced severe oxidative liver damage in Nrf2 knockout mice but not in wild type mice. Activities and levels of CYP2E1 and 2A5 were elevated by pyrazole in the wild type mice but not in the Nrf2 knockout mice. However, expression or activity of Nrf2-regulated antioxidant enzymes, such as gamma-glutamylcysteine synthetase (GCS), heme oxygenase-1 (HO-1) and glutathione-S-transferase (GST), were upregulated in the pyrazole-treated wild type mice, but to a lesser extent or not at all in the pyrazole-treated Nrf2 knockout mice. Treatment with antioxidants such as vitamin C or S-adenosyl-l-methionine (SAM) or an inhibitor of iNOS prevented the pyrazole-induced oxidative liver damage, thus validating the role of oxidative/nitrosative stress in the pyrazole induced liver injury to the Nrf2 knockout mice. In summary, even though ROS-producing CYP2E1/2A5 were not elevated by pyrazole, impaired antioxidant capacity resulting from Nrf2 deficiency appear to be sufficient to promote pyrazole-induced oxidative liver injury.

Authors+Show Affiliations

Department of Pharmacology and Systems Therapeutics, Mount Sinai School of Medicine, New York, NY 10029, USA.No affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

18721845

Citation

Lu, Yongke, et al. "Pyrazole Induced Oxidative Liver Injury Independent of CYP2E1/2A5 Induction Due to Nrf2 Deficiency." Toxicology, vol. 252, no. 1-3, 2008, pp. 9-16.
Lu Y, Gong P, Cederbaum AI. Pyrazole induced oxidative liver injury independent of CYP2E1/2A5 induction due to Nrf2 deficiency. Toxicology. 2008;252(1-3):9-16.
Lu, Y., Gong, P., & Cederbaum, A. I. (2008). Pyrazole induced oxidative liver injury independent of CYP2E1/2A5 induction due to Nrf2 deficiency. Toxicology, 252(1-3), 9-16. https://doi.org/10.1016/j.tox.2008.07.058
Lu Y, Gong P, Cederbaum AI. Pyrazole Induced Oxidative Liver Injury Independent of CYP2E1/2A5 Induction Due to Nrf2 Deficiency. Toxicology. 2008 Oct 30;252(1-3):9-16. PubMed PMID: 18721845.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Pyrazole induced oxidative liver injury independent of CYP2E1/2A5 induction due to Nrf2 deficiency. AU - Lu,Yongke, AU - Gong,Pengfei, AU - Cederbaum,Arthur I, Y1 - 2008/08/03/ PY - 2008/05/09/received PY - 2008/07/05/revised PY - 2008/07/17/accepted PY - 2008/8/30/pubmed PY - 2009/1/6/medline PY - 2008/8/30/entrez SP - 9 EP - 16 JF - Toxicology JO - Toxicology VL - 252 IS - 1-3 N2 - Pyrazole can induce CYP2E1 and 2A5, which produce reactive oxygen species (ROS). Nuclear factor erythroid 2-related factor 2 (Nrf2) regulates important antioxidant enzymes to remove ROS. In this study, we applied Nrf2 knockout mice to test the hypothesis that pyrazole will cause hepatotoxicity and elevate oxidative stress to a greater extent in Nrf2 knockout mice compared to wild type mice. Pyrazole induced severe oxidative liver damage in Nrf2 knockout mice but not in wild type mice. Activities and levels of CYP2E1 and 2A5 were elevated by pyrazole in the wild type mice but not in the Nrf2 knockout mice. However, expression or activity of Nrf2-regulated antioxidant enzymes, such as gamma-glutamylcysteine synthetase (GCS), heme oxygenase-1 (HO-1) and glutathione-S-transferase (GST), were upregulated in the pyrazole-treated wild type mice, but to a lesser extent or not at all in the pyrazole-treated Nrf2 knockout mice. Treatment with antioxidants such as vitamin C or S-adenosyl-l-methionine (SAM) or an inhibitor of iNOS prevented the pyrazole-induced oxidative liver damage, thus validating the role of oxidative/nitrosative stress in the pyrazole induced liver injury to the Nrf2 knockout mice. In summary, even though ROS-producing CYP2E1/2A5 were not elevated by pyrazole, impaired antioxidant capacity resulting from Nrf2 deficiency appear to be sufficient to promote pyrazole-induced oxidative liver injury. SN - 0300-483X UR - https://www.unboundmedicine.com/medline/citation/18721845/Pyrazole_induced_oxidative_liver_injury_independent_of_CYP2E1/2A5_induction_due_to_Nrf2_deficiency_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0300-483X(08)00355-7 DB - PRIME DP - Unbound Medicine ER -