CYP2E1 Sensitizes the Liver to LPS- and TNF α-Induced Toxicity via Elevated Oxidative and Nitrosative Stress and Activation of ASK-1 and JNK Mitogen-Activated Kinases
Pyrazole potentiates TNFα hepatotoxicity and oxidative stress in mice. Mice were treated with either saline or pyrazole alone or TNFα alone or pyrazole plus TNFα followed by assays for (a) serum ALT/AST, (b) histopathology (arrows show necrotic zones), (c) lipid peroxidation as reflected by levels of TBARs in liver cell lysates and in isolated mitochondrial fractions. Note: combined treatment with TNFα plus pyrazole produces liver injury. (d) Serum ALT and AST levels in pyrazole plus TNFα-treated wild type (WT) and CYP2E1 knockout (KO) mice. (e) Histopathology in pyrazole plus TNFα-treated KO (panel A) and WT (panel B). Note: liver injury is decreased in CYP2E1 knockout mice compared to WT mice.
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