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Inhibition of the mitochondrial permeability transition by cyclosporin A prevents pyrazole plus lipopolysaccharide-induced liver injury in mice.
Free Radic Biol Med. 2009 Feb 01; 46(3):406-13.FR

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+Show Affiliations

Department of Pharmacology and Systems Therapeutics, Mount Sinai School of Medicine, New York, NY 10029, USA. zhugejian@yahoo.comNo affiliation info available

Pub Type(s)

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

Language

eng

PubMed ID

19026739

Citation

Zhuge, Jian, and Arthur I. Cederbaum. "Inhibition of the Mitochondrial Permeability Transition By Cyclosporin a Prevents Pyrazole Plus Lipopolysaccharide-induced Liver Injury in Mice." Free Radical Biology & Medicine, vol. 46, no. 3, 2009, pp. 406-13.
Zhuge J, Cederbaum AI. Inhibition of the mitochondrial permeability transition by cyclosporin A prevents pyrazole plus lipopolysaccharide-induced liver injury in mice. Free Radic Biol Med. 2009;46(3):406-13.
Zhuge, J., & Cederbaum, A. I. (2009). Inhibition of the mitochondrial permeability transition by cyclosporin A prevents pyrazole plus lipopolysaccharide-induced liver injury in mice. Free Radical Biology & Medicine, 46(3), 406-13. https://doi.org/10.1016/j.freeradbiomed.2008.10.037
Zhuge J, Cederbaum AI. Inhibition of the Mitochondrial Permeability Transition By Cyclosporin a Prevents Pyrazole Plus Lipopolysaccharide-induced Liver Injury in Mice. Free Radic Biol Med. 2009 Feb 1;46(3):406-13. PubMed PMID: 19026739.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Inhibition of the mitochondrial permeability transition by cyclosporin A prevents pyrazole plus lipopolysaccharide-induced liver injury in mice. AU - Zhuge,Jian, AU - Cederbaum,Arthur I, Y1 - 2008/10/31/ PY - 2008/08/18/received PY - 2008/09/29/revised PY - 2008/10/22/accepted PY - 2008/11/26/pubmed PY - 2009/9/26/medline PY - 2008/11/26/entrez SP - 406 EP - 13 JF - Free radical biology & medicine JO - Free Radic Biol Med VL - 46 IS - 3 N2 - 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. SN - 1873-4596 UR - https://www.unboundmedicine.com/medline/citation/19026739/Inhibition_of_the_mitochondrial_permeability_transition_by_cyclosporin_A_prevents_pyrazole_plus_lipopolysaccharide_induced_liver_injury_in_mice_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0891-5849(08)00664-3 DB - PRIME DP - Unbound Medicine ER -