Inhibition of the mitochondrial permeability transition by cyclosporin A prevents pyrazole plus lipopolysaccharide-induced liver injury in mice.

Abstract

Previous results showed that pyrazole potentiates lipopolysaccharide (LPS)-induced liver injury in mice. Mechanisms involved the overexpression of cytochrome P450 2E1 (CYP2E1), oxidative stress, and activation of c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK). The current study was carried out to test the hypothesis that the mitochondria permeability transition (MPT) plays a role in this pyrazole plus LPS toxicity. Mice were injected intraperitoneally with pyrazole for 2 days, followed by a challenge with LPS with or without treatment with cyclosporin A (CsA), an inhibitor of the MPT. Serum alanine aminotransferase and aspartate aminotransferase were increased by pyrazole plus LPS treatment, and CsA treatment could attenuate these increases. CsA also prevented pyrazole plus LPS-induced hepatocyte necrosis. Formation of 4-hydroxynonenal protein adducts and 3-nitrotyrosine protein adducts in liver tissue was increased by the pyrazole plus LPS treatment, and CsA treatment blunted these increases. Swelling, cytochrome c release from mitochondria to the cytosol, and lipid peroxidation were increased in mitochondria isolated from the pyrazole plus LPS-treated mice, and CsA treatment prevented these changes. CsA did not prevent the increased levels of inducible nitric oxide synthase (iNOS), tumor necrosis factor-alpha (TNF-alpha), pp38 MAPK, and p-JNK2. In conclusion, although CsA does not prevent elevations in upstream mediators of the pyrazole plus LPS toxicity (iNOS, TNF-alpha, CYP2E1, MAPK), it does protect mice from the pyrazole plus LPS-induced liver toxicity by preventing the MPT and release of cytochrome c and decreasing mitochondrial oxidative stress. These results indicate that mitochondria are the critical targets of pyrazole plus LPS in mediating liver injury.

• Authors: Jian Zhuge, Arthur I Cederbaum
• Journal: Free radical biology & medicine (Free Radic Biol Med) Vol. 46 Issue 3 Pg. 406-13 (Feb 01 2009) ISSN: 1873-4596 [Electronic] United States
• PMID: 19026739 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Lipopolysaccharides
• Mitochondrial Membrane Transport Proteins
• Mitochondrial Permeability Transition Pore
• Proto-Oncogene Proteins c-bcl-2
• Pyrazoles
• pyrazole
• Cyclosporine
• Aspartate Aminotransferases
• Alanine Transaminase
• Mitogen-Activated Protein Kinase 9
• p38 Mitogen-Activated Protein Kinases

Topics

• Alanine Transaminase (antagonists & inhibitors)
• Animals
• Aspartate Aminotransferases (antagonists & inhibitors)
• Chemical and Drug Induced Liver Injury
• Cyclosporine (administration & dosage)
• Lipid Peroxidation (drug effects)
• Lipopolysaccharides (toxicity)
• Liver (enzymology, pathology)
• Liver Diseases (pathology, prevention & control)
• Mice
• Mice, Inbred C57BL
• Mitochondria, Liver (metabolism, pathology)
• Mitochondrial Membrane Transport Proteins (antagonists & inhibitors)
• Mitochondrial Permeability Transition Pore
• Mitogen-Activated Protein Kinase 9 (genetics, metabolism)
• Necrosis
• Oxidative Stress
• Proto-Oncogene Proteins c-bcl-2 (genetics, metabolism)
• Pyrazoles (toxicity)
• Signal Transduction (drug effects)
• p38 Mitogen-Activated Protein Kinases (genetics, metabolism)