title: Carbon tetrachloride-mediated lipid peroxidation induces early mitochondrial alterations in mouse liver.
abstract: Although carbon tetrachloride (CCl(4))-induced acute and chronic hepatotoxicity have been extensively studied, little is known about the very early in vivo effects of this organic solvent on oxidative stress and mitochondrial function. In this study, mice were treated with CCl(4) (1.5 ml/kg ie 2.38 g/kg) and parameters related to liver damage, lipid peroxidation, stress/defense and mitochondria were studied 3 h later. Some CCl(4)-intoxicated mice were also pretreated with the cytochrome P450 2E1 inhibitor diethyldithiocarbamate or the antioxidants Trolox C and dehydroepiandrosterone. CCl(4) induced a moderate elevation of aminotransferases, swelling of centrilobular hepatocytes, lipid peroxidation, reduction of cytochrome P4502E1 mRNA levels and a massive increase in mRNA expression of heme oxygenase-1 and heat shock protein 70. Moreover, CCl(4) intoxication induced a severe decrease of mitochondrial respiratory chain complex IV activity, mitochondrial DNA depletion and damage as well as ultrastructural alterations. Whereas DDTC totally or partially prevented all these hepatic toxic events, both antioxidants protected only against liver lipid peroxidation and mitochondrial damage. Taken together, our results suggest that lipid peroxidation is primarily implicated in CCl(4)-induced early mitochondrial injury. However, lipid peroxidation-independent mechanisms seem to be involved in CCl(4)-induced early hepatocyte swelling and changes in expression of stress/defense-related genes. Antioxidant therapy may not be an efficient strategy to block early liver damage after CCl(4) intoxication.
authors.affiliation: INSERM, UMR 991, Liver Metabolisms and Cancer, Rennes, France.
authors.forename: Laetitia
authors.initials: L
authors.lastname: Knockaert
authors.forename: Alain
authors.initials: A
authors.lastname: Berson
authors.forename: Catherine
authors.initials: C
authors.lastname: Ribault
authors.forename: Pierre-Emmanuel
authors.initials: PE
authors.lastname: Prost
authors.forename: Alain
authors.initials: A
authors.lastname: Fautrel
authors.forename: Julie
authors.initials: J
authors.lastname: Pajaud
authors.forename: Sylvie
authors.initials: S
authors.lastname: Lepage
authors.forename: Catherine
authors.initials: C
authors.lastname: Lucas-Clerc
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Bégué
authors.forename: Bernard
authors.initials: B
authors.lastname: Fromenty
authors.forename: Marie-Anne
authors.initials: MA
authors.lastname: Robin
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D002251:Carbon Tetrachloride; D002252:Carbon Tetrachloride Poisoning / Q000378:metabolism*; D002839:Chromans / Q000494:pharmacology; D065691:Cytochrome P-450 CYP2E1 Inhibitors; D003687:Dehydroepiandrosterone / Q000494:pharmacology; D004050:Ditiocarb / Q000494:pharmacology; D022781:Hepatocytes / Q000187:drug effects*; D015227:Lipid Peroxidation / Q000187:drug effects*; D008297:Male; D051379:Mice; D008930:Mitochondria, Liver / Q000187:drug effects / Q000378:metabolism*
chemical_list: D000975:Antioxidants; D002839:Chromans; D065691:Cytochrome P-450 CYP2E1 Inhibitors; D003687:Dehydroepiandrosterone; D004050:Ditiocarb; D002251:Carbon Tetrachloride; C010643:6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid