Comparison of cytotoxicity induced by hypolipidemic drugs via reactive oxygen species in human and rodent liver cells.
Hypolipidemic drugs (HP drugs) are xenobiotics belonging to the peroxisome proliferator family which are used as pharmaceuticals in the treatment of human hyperlipidemia and hypercholesterolemia. They cause hepatocarcinogenesis in rodents by increasing cell proliferation. One hypothesis is that this hepatocarcinogenic effect is caused by induced oxidative stress resulting from the overproduction of reactive oxygen species (ROS) and from a decreasing antioxidant defense. In addition, ROS play a role in hepatocellular proliferation by activation of NF-kappaB and AP-1, leading to an increase in mitogenic cytokines such as tumor necrosis factor-alpha. No liver cancer incidence has been noted in individuals treated with HP drugs for brief periods of time. However, the observation that old rats and mice are more susceptible than young individuals to the hepatocarcinogenic effect caused by long term exposure to HP drugs raises the question of a potential health risk for the human population. In vitro, HP drugs cause an apoptogenic effect in human hepatocytes. This effect is related to a moderate antioxidant response, dysfunction of mitochondria caused by an overproduction of ROS and release of apoptogenic factors. Finally, the apoptogenic effect of HP drugs is observed in human hepatomas, suggesting a clinical interest of these agents in antitumoral activity.
Becuwe
Philippe
P
Laboratoire de Biologie Cellulaire du Développement, EA 3446 Proliférateurs de Peroxysomes, Université Henri Poincaré-Nancy I, Faculté des Sciences, Vandoeuvre-lés-Nancy, France. becuwe@scbiol.u-nancy.fr
Dauça
Michel
M
D000367:Age Factors; D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D006801:Humans; D006949:Hyperlipidemias / Q000188:drug therapy; D000960:Hypolipidemic Agents / Q000009:adverse effects* / Q000627:therapeutic use; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013482:Superoxide Dismutase / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D000975:Antioxidants; D000960:Hypolipidemic Agents; D016328:NF-kappa B; D017382:Reactive Oxygen Species; D018808:Transcription Factor AP-1; D014409:Tumor Necrosis Factor-alpha; D013482:Superoxide Dismutase