Mechanism of phthalate-induced inhibition of hepatic mitochondrial beta-oxidation.

Studies show that peroxisome proliferators inhibit mitochondrial beta-oxidation 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 livers from rats pre-treated with diethylhexyl phthalate (DEHP) compared with livers from control rats. Monethylhexyl phthalate (MEHP; 200 microM), a primary metabolite of DEHP and a known peroxisome proliferator, inhibited the oxidation of palmitic acid as well as its acyl-CoA and acylcarnitine derivatives in isolated mitochondria by about 50-60%. Similar concentrations of MEHP also inhibited mitochondrial respiration of succinate and malate plus glutamate. However, respiration of ascorbate was not influenced by MEHP. Considering the assembly of the mitochondrial 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 peroxisome proliferation.