Effect of glycine on valproate toxicity in rat hepatocytes

The interaction between the amino acid glycine and valproate (VPA), an antiepileptic drug (AED) that occasionally causes hepatotoxicity, was studied in rat hepatocytes in monolayer culture. Valproate caused a dose-dependent increase in leakage of lactic acid dehydrogenase (LDH), and glycine prevented this toxic response. L-Carnitine, L-alanine, and L-cysteine did not protect hepatocytes from VPA. Glycine also partially antagonized inhibition of fatty acid beta-oxidation by VPA, as estimated by the generation of acid-soluble products from [14C]palmitic acid. These results are consistent with the hypothesis that glycine prevents VPA toxicity by removing acyl-CoA esters, which accumulate during VPA exposure and interfere with fatty acid beta-oxidation. Glycine, however, also antagonized the toxic effects of acetaminophen on hepatocytes, although at higher concentrations than required to protect hepatocytes from VPA. Because the mechanism of toxicity of acetaminophen probably is different from that of VPA, a nonspecific cytoprotective effect may contribute to glycine antagonism of valproate toxicity. Our results emphasize the importance of glycine in protecting hepatocytes from noxious insult in general as well as from VPA in particular.