MECHANISM OF PHTHALATE-INDUCED INHIBITION OF HEPATIC MITOCHONDRIAL BETA-OXIDATION

Studies show that peroxisome proliferators inhibit mitochondrial P-oxi dation of fatty acids. However, mechanism(s) of this inhibitory effect has not been identified. This study was undertaken to delineate such mechanism(s). Ketogenesis was significantly diminished in perfused liv ers from rats pre-treated with diethylhexyl phthalate (DEHP) compared with livers from control rats. Monoethylhexyl phthalate (MEHP; 200 mu M), a primary metabolite of DEHP and a known peroxisome proliferator, inhibited the oxidation of palmitic acid as well as its acyl-CoA and a cylcarnitine derivatives in isolated mitochondria by about 50-60%. Sim ilar concentrations of MEHP also inhibited mitochondrial respiration o f succinate and malate plus glutamate. However, respiration of ascorba te was not influenced by MEHP. Considering the assembly of the mitocho ndrial respiratory chain, these data indicate that phthalates inhibit fatty acid metabolism as a result of inhibiting the respiratory chain at the level of the cytochrome c reductase. This effect may represent an early step in the mechanism by which phthalates cause hepatic perox isome proliferation.