Effects of salicylate on hepatocyte lactate metabolism.

We have examined the effects of salicylate on fluxes of lactate metabolism in rat hepatocytes using a steady state model. Salicylate produces an uncoupling effect, an inhibition of gluconeogenesis, a marked activation of pyruvate dehydrogenase flux, and an inhibition of endogenous fatty acid oxidation. Agents with known functions such as dinitrophenol and dichloroacetate were also compared in this system. The in vitro inhibition of gluconeogenesis caused by salicylate is not primarily related to the uncoupling effect. The fact that octanoate, but not palmitate, overcomes the salicylate inhibition of gluconeogenesis suggests that salicylyl CoA is involved in the inhibition. To relate in vitro studies to Reye's syndrome in vivo, in which medium chain dicarboxylic acids accumulate, we have also examined the effects of monomethyl suberate on liver lactate metabolism. This half ester is taken up by the hepatocytes, and causes inhibition of lactate gluconeogenesis, and uncoupling. Both salicylate and monomethyl suberate inhibit the oxidation of 0.2 mM octanoate by hepatocytes.