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 d ose-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 partial ly antagonized inhibition of fatty acid beta-oxidation by VPA, as esti mated by the generation of acid-soluble products from [C-14]palmitic a cid. These results are consistent with the hypothesis that glycine pre vents VPA toxicity by removing acyl-CoA esters, which accumulate durin g VPA exposure and interfere with fatty acid beta-oxidation. Glycine, however, also antagonized the toxic effects of acetaminophen on hepato cytes, although at higher concentrations than required to protect hepa tocytes from VPA. Because the mechanism of toxicity of acetaminophen p robably is different from that of VPA, a nonspecific cytoprotective ef fect may contribute to glycine antagonism of valproate toxicity. Our r esults emphasize the importance of glycine in protecting hepatocytes f rom noxious insult in general as well as from VPA in particular.