Metabolic effects of pivalate in isolated rat hepatocytes

Pivalate (trimethylacetic acid) administration in humans or rat has been reported to cause metabolic changes and increased urinary carnitine excretion secondary to pivaloylcarnitine generation. As pivaloylcarnitine formation is dependent on intracellular activation of pivalate, the effects of pivalate on cellular coenzyme A and acyl-CoA contents and oxidative metabolism were defined using isolated rat hepatocytes. During incubations with pivalate (1.0 mM), hepatocyte coenzyme A content fell to less than 0.05 nmol/10(6) cells (vs 0.97 nmol/10(6) cells in the absence of pivalate) as pivaloyl-CoA accumulated. Pivalate (5 mM) inhibited 14CO2 generation from 10 mM [1-14C]pyruvate by 34%, but had no effect on 0.8 mM [1-14C]palmitate oxidation. Pivaloyl-CoA was a substrate for hepatocyte carnitine acyltransferase activity, but supported acylcarnitine formation at rates only 10-20% of those observed with equimolar acetyl-CoA or isovaleryl-CoA as substrates. Thus, hepatocytes activate pivalate to pivaloyl-CoA, which can then be used as a substrate for pivaloylcarnitine formation. The sequestration of hepatocyte coenzyme A as pivaloyl-CoA is associated with inhibition of pyruvate oxidation. As with other organic carboxylic acids, activation of pivalate to the coenzyme A thioester is an important aspect in the biochemical toxicology of the compound.