Pyrazole induced oxidative liver injury independent of CYP2E1/2A5 induction due to Nrf2 deficiency.

Toxicology
Yongke LuArthur Cederbaum

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-producin...Continue Reading

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Citations

Nov 6, 2010·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Yongke LuArthur I Cederbaum
Oct 6, 2010·Marine Biotechnology·Il-Hwa HongKyu-Shik Jeong
May 4, 2012·Toxicological Sciences : an Official Journal of the Society of Toxicology·Yongke LuArthur I Cederbaum
Apr 12, 2012·Antioxidants & Redox Signaling·Soo Han BaeSue Goo Rhee
Aug 13, 2009·Expert Opinion on Drug Metabolism & Toxicology·Arthur Cederbaum
Nov 29, 2011·World Neurosurgery·Hao PanXingfen Su
Sep 14, 2015·Naunyn-Schmiedeberg's Archives of Pharmacology·Feng HongYongke Lu
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Dec 6, 2014·Toxicology and Applied Pharmacology·Siti Nur Fadzilah MuhsainA'edah Abu-Bakar
Jun 25, 2013·Food and Chemical Toxicology : an International Journal Published for the British Industrial Biological Research Association·Jing-Jing YangJun Li
Oct 31, 2016·Environmental Toxicology and Pharmacology·Meng WangXiaoying Zhang
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Aug 18, 2012·Human & Experimental Toxicology·N ArnalC A Marra

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