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Cyclosporine A protects against arachidonic acid toxicity in rat hepatocytes: role of CYP2E1 and mitochondria.
Hepatology. 2002 Jun; 35(6):1420-30.Hep

Abstract

Diets high in polyunsaturated fatty acids (PUFA) are important for the development of alcoholic liver injury. The goal of this report was to characterize toxicity by arachidonic acid (AA), its enhancement by salicylate, and the role of mitochondrial injury in the pathway leading to toxicity in hepatocytes from pyrazole-treated rats. AA caused toxicity that was increased by sodium salicylate. This synergistic toxicity was reduced by diallyl sulfide (DAS), an inhibitor of CYP2E1; Trolox ([+/-] 6-hydroxy, 2, 5, 7, 8-tetramethylchroman-2-carboxylic acid), an inhibitor of lipid peroxidation; Z-Val-Ala-Asp(OMe)-fluoromethylketone (ZVAD-FMK), a pan caspase inhibitor; and by cyclosporine A (CsA), an inhibitor of the mitochondrial permeability transition. Mitochondrial membrane potential also was reduced, and this was prevented by cyclosporine, diallyl sulfide, and Trolox. There was release of mitochondrial cytochrome c into the cytosol and activation of caspase 3, which were prevented by cyclosporine, diallylsulfide, and Trolox. Toxicity was prevented by expression of catalase either in the cytosolic or the mitochondrial compartment. Levels of CYP2E1 rapidly declined, and this was partially prevented by salicylate. These results are consistent with a model in which CYP2E1-dependent production of reactive oxygen species enhances lipid peroxidation when AA is added to hepatocytes. This results in damage to the mitochondria, with initiation of a membrane permeability transition and a decline in membrane potential, followed by release of cytochrome c, caspase 3 activation, and cellular toxicity. In conclusion, damage to mitochondria appears to play an important role in the CYP2E1 plus AA toxicity.

Authors+Show Affiliations

Department of Pharmacology and Biological Chemistry, Mount Sinai School of Medicine, New York University, New York, NY 10029, USA.No affiliation info available

Pub Type(s)

Journal Article
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

12029627

Citation

Wu, Defeng, and Arthur I. Cederbaum. "Cyclosporine a Protects Against Arachidonic Acid Toxicity in Rat Hepatocytes: Role of CYP2E1 and Mitochondria." Hepatology (Baltimore, Md.), vol. 35, no. 6, 2002, pp. 1420-30.
Wu D, Cederbaum AI. Cyclosporine A protects against arachidonic acid toxicity in rat hepatocytes: role of CYP2E1 and mitochondria. Hepatology. 2002;35(6):1420-30.
Wu, D., & Cederbaum, A. I. (2002). Cyclosporine A protects against arachidonic acid toxicity in rat hepatocytes: role of CYP2E1 and mitochondria. Hepatology (Baltimore, Md.), 35(6), 1420-30.
Wu D, Cederbaum AI. Cyclosporine a Protects Against Arachidonic Acid Toxicity in Rat Hepatocytes: Role of CYP2E1 and Mitochondria. Hepatology. 2002;35(6):1420-30. PubMed PMID: 12029627.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Cyclosporine A protects against arachidonic acid toxicity in rat hepatocytes: role of CYP2E1 and mitochondria. AU - Wu,Defeng, AU - Cederbaum,Arthur I, PY - 2002/5/25/pubmed PY - 2002/6/22/medline PY - 2002/5/25/entrez SP - 1420 EP - 30 JF - Hepatology (Baltimore, Md.) JO - Hepatology VL - 35 IS - 6 N2 - Diets high in polyunsaturated fatty acids (PUFA) are important for the development of alcoholic liver injury. The goal of this report was to characterize toxicity by arachidonic acid (AA), its enhancement by salicylate, and the role of mitochondrial injury in the pathway leading to toxicity in hepatocytes from pyrazole-treated rats. AA caused toxicity that was increased by sodium salicylate. This synergistic toxicity was reduced by diallyl sulfide (DAS), an inhibitor of CYP2E1; Trolox ([+/-] 6-hydroxy, 2, 5, 7, 8-tetramethylchroman-2-carboxylic acid), an inhibitor of lipid peroxidation; Z-Val-Ala-Asp(OMe)-fluoromethylketone (ZVAD-FMK), a pan caspase inhibitor; and by cyclosporine A (CsA), an inhibitor of the mitochondrial permeability transition. Mitochondrial membrane potential also was reduced, and this was prevented by cyclosporine, diallyl sulfide, and Trolox. There was release of mitochondrial cytochrome c into the cytosol and activation of caspase 3, which were prevented by cyclosporine, diallylsulfide, and Trolox. Toxicity was prevented by expression of catalase either in the cytosolic or the mitochondrial compartment. Levels of CYP2E1 rapidly declined, and this was partially prevented by salicylate. These results are consistent with a model in which CYP2E1-dependent production of reactive oxygen species enhances lipid peroxidation when AA is added to hepatocytes. This results in damage to the mitochondria, with initiation of a membrane permeability transition and a decline in membrane potential, followed by release of cytochrome c, caspase 3 activation, and cellular toxicity. In conclusion, damage to mitochondria appears to play an important role in the CYP2E1 plus AA toxicity. SN - 0270-9139 UR - https://www.unboundmedicine.com/medline/citation/12029627/Cyclosporine_A_protects_against_arachidonic_acid_toxicity_in_rat_hepatocytes:_role_of_CYP2E1_and_mitochondria_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S027091390210067X DB - PRIME DP - Unbound Medicine ER -