Inhibition of palmitoyl co-enzyme A hydrolase in mitochondria and microsomes by pharmaceutical organic anions.

Rat microsomes and mitochondria were isolated and incubated with selected pharmaceutical organic anions at concentrations of 0, 0.2, 0.5, 1.0, and 2 mM. Activity of palmitoyl CoA hydrolase (PCAH) was shown to be reduced in a dose-dependent manner in microsomes by ibuprofen, valproate, acetyl salicylate, 2,4-dichlorophenoxyacetate (2,4-D), and 4-pentenoate, but not salicylate. Mitochondrial PCAH activity was inhibited by clofibrate, ibuprofen, valproate, and 2,4-D. Mitochondrial oxidative phosphorylation was impaired or uncoupled by each of the mitochondrial PCAH inhibitors. The inhibition of PCAH by some of these agents may lead to fatty acyl CoA accumulation. Very low concentrations of fatty acyl CoA are known to cause mitochondrial uncoupling and increase permeability. This action may play a role in the mitochondrial injury caused by some of these agents or related disease processes.