No 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.

There has been growing evidence that phase I metabolizing enzymes cytochromes P450 (CYPs) are not only located in the endoplasmic reticulum but also in other subcellular compartments and particularly in mitochondria. The presence of CYPs in these organelles raises questions regarding their metabolic role and their possible deleterious effects on the respiratory chain complexes and mitochondrial DNA. This review will focus on one particular CYP, CYP2E1, which represents a significant source of reactive oxygen species and is involved in the metabolism of small molecule substrates including ethanol, drugs and carcinogens. Since hepatic CYP2E1 expression is increased in different physiopathological situations such as type 2 diabetes, obesity and ethanol intoxication, the presence of significant levels of this CYP within the mitochondria could have major deleterious effects. This review recalls the main data that brought to the fore the presence of CYP2E1 in mitochondria and the mechanism of its targeting in this organelle. The potential pathological consequences linked to the presence of CYP2E1 in mitochondria will be subsequently discussed.