Mitochondrial damage by the "pro-oxidant" peroxisomal proliferator clofibrate

Clofibrate is a peroxisome proliferator that can cause hepatic cancer in ro dents. It has been suggested that oxidative damage is involved in this hepa tocarcinogenesis, although the data are conflicting. We confirmed that clof ibrate causes oxidative damage in nuclei from the livers of mice treated wi th this substance, measured both as protein carbonyls and levels of 8-hydro xy-2'-deoxyguanosine (g-OHdG) in DNA. In addition, clofibrate also affects mitochondria, causing elevated levels of carbonyls and 8-OHdG, increased st ate 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. (C) 1999 Elsevi er Science Inc.