Mitochondrial damage by the “pro-oxidant” peroxisomal proliferator clofibrate

Clofibrate is a peroxisome proliferator that can cause hepatic cancer in rodents. It has been suggested that oxidative damage is involved in this hepatocarcinogenesis, although the data are conflicting. We confirmed that clofibrate causes oxidative damage in nuclei from the livers of mice treated with this substance, measured both as protein carbonyls and levels of 8-hydroxy-2′-deoxyguanosine (8-OHdG) in DNA. In addition, clofibrate also affects mitochondria, causing elevated levels of carbonyls and 8-OHdG, increased state 4 respiration and decreased adenosine triphosphatase (ATPase) activity. No evidence for clofibrate-induced lipid peroxidation in mitochondria was obtained. We propose that mitochondria may be a major target of injury and a source of oxidative stress in clofibrate-treated animals.