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Titolo:
Mechanism of clofibrate hepatotoxicity: Mitochondrial damage and oxidativestress in hepatocytes
Autore:
Qu, B; Li, QT; Wong, KP; Tan, TMC; Halliwell, B;
Indirizzi:
Natl Univ Singapore, Fac Med, Dept Biochem, Singapore 1191260, Singapore Natl Univ Singapore Singapore Singapore 1191260 apore 1191260, Singapore
Titolo Testata:
FREE RADICAL BIOLOGY AND MEDICINE
fascicolo: 5, volume: 31, anno: 2001,
pagine: 659 - 669
SICI:
0891-5849(20010901)31:5<659:MOCHMD>2.0.ZU;2-K
Fonte:
ISI
Lingua:
ENG
Soggetto:
PERMEABILITY TRANSITION PORE; ACTIVATED RECEPTOR-ALPHA; ELECTRON-TRANSPORT CHAIN; PROGRAMMED CELL-DEATH; PEROXISOME PROLIFERATORS; RAT HEPATOCYTES; CYCLOSPORINE-A; REPERFUSION INJURY; CYTOCHROME-C; APOPTOSIS;
Keywords:
clofibrate; peroxisome proliferators; mitochondrial membrane potential; MPT; oxidative stress; apoptosis; free radicals;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
63
Recensione:
Indirizzi per estratti:
Indirizzo: Halliwell, B Natl Univ Singapore, Fac Med, Dept Biochem, 10 Kent Ridge Crescent, Singapore 1191260, Singapore Natl Univ Singapore 10 Kent Ridge Crescent Singapore Singapore 1191260
Citazione:
B. Qu et al., "Mechanism of clofibrate hepatotoxicity: Mitochondrial damage and oxidativestress in hepatocytes", FREE RAD B, 31(5), 2001, pp. 659-669

Abstract

Peroxisome proliferators have been found to induce hepatocarcinogenesis inrodents, and may cause mitochondrial damage. Consistent with this, clofibrate increased hepatic mitochondrial oxidative DNA and protein damage in mice. The present investigation aimed to study the mechanism by which this might occur by examining the effect of clofibrate on freshly isolated mouse liver mitochondria and a cultured hepatocyte cell line, AML-12. Mitochondrialmembrane potential (Delta Psi (m)) was determined by using the fluorescentdye 5,5',6,6'-tetrachloro-1,1', 3,3'-tetraethyl-benzimidazolylcarbocyanineiodide (JC-1) and tetramethylrhodamine methyl ester (TMRM). Application ofclofibrate at concentrations greater than 0.3 mM rapidly collapsed the Delta Psi (m) both in liver cells and in isolated mitochondria. The loss of Delta Psi (m) occurred prior to cell death and appeared to involve the mitochondrial permeability transition (MPT), as revealed by calcein fluorescence studies and the protective effect of cyclosporin A (CsA) on the decrease inDelta Psi (m). Levels of reactive oxygen species (ROS) were measured with the fluorescent probes 5-(and-6)carboxy-2',7'-dichlorofluoreseein diacetate(DCFDA) and dihydrorhodamine 123 (DHR123). Treatment of the hepatocytes with clofibrate caused a significant increase in intracellular and mitochondrial ROS. Antioxidants such as vitamin C, deferoxamine, and catalase were able to protect the cells against the clofibrate-induced loss of viability, as was CsA, but to a lesser extent. These results suggest that one action ofclofibrate might be to impair mitochondrial function, so stimulating formation of ROS, which eventually contribute to cell death. (C) 2001 Elsevier Science Inc.

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Documento generato il 23/01/20 alle ore 18:18:40