Cytochrome P4502E1 sensitizes to tumor necrosis factor alpha-induced liver injury through activation of mitogen-activated protein kinases in mice

The goal of this study was to evaluate the role of mitogen-activated protein kinase (MAPK) in cytochrome P4502E1 (CYP2E1) potentiation of lipopolysaccharide or tumor necrosis factor alpha (TNF-alpha)-induced liver injury. Treatment of C57/BL/6 mice with pyrazole (PY) plus lipopolysaccharide (LPS) induced liver injury compared with mice treated with PY or LPS alone. The c-Jun N-terminal kinase (JNK) inhibitor SP600125 or p38 MAPK inhibitor SB203580 prevented this liver injury. PY plus LPS treatment activated p38 MAPK and JNK but not extracellular signal-regulated kinase (ERK). PY plus LPS treatment triggered oxidative stress in the liver with increases in lipid peroxidation, decrease of glutathione (GSH) levels, and increased production of 3-nitrotyrosine adducts and protein carbonyl formation. This oxidative stress was blocked by SP600125 or SB203580. PY plus LPS treatment elevated TNF-alpha production, and this was blocked by SP600125 or SB203580. Neither SP600125 nor SB203580 affected CYP2E1 activity or protein levels. Treating C57/BL/6 mice with PY plus TNF-alpha also induced liver injury and increased lipid peroxidation and decreased GSH levels. Prolonged activation of JNK and p38 MAPK was observed. All of these effects were blocked by SP600125 or SB203580. In contrast to wild-type SV 129 mice, treating CYP2E1 knockout mice with PY plus TNF-alpha did not induce liver injury, thus validating the role of CYP21E1 in this potentiated liver injury. Liver mitochondria from PY plus LPS or PY plus TNF-alpha treated mice underwent calcium-dependent, cyclosporine A-sensitive swelling, which was prevented by SB203580 or SP600125.These results show that CYP2E1 sensitizes liver hepatocytes to LPS or TNF-alpha and that the CYP2E1-enhanced LPS or TNF-alpha injury, oxidant stress, and mitochondrial injury is JNK or p38 MAPK dependent.