Toxic effect of valproic acid on tryptophan binding to rat hepatic nuclei

Abstract

This study evaluated whether valproic acid, a branched-chain fatty acid which has been used in the treatment of seizures, would influence the binding of l-tryptophan to rat hepatic nuclei. Previous studies have indicated that binding of l-tryptophan to hepatic nuclear envelope protein was saturable, stereospecific, and of high affinity. In this study, we investigated whether valproic acid, which under certain conditions is heptatoxic, would influence l-tryptophan binding to rat hepatic nuclei as assayed by in vitro l-(5- 3H)tryptophan binding. Our results indicate that the addition of valproic acid to hepatic nuclei or nuclear envelopes in vitro has little influence on their l-(5- 3H)tryptophan binding. On the other hand, when valproic acid (80 mg/100 g body weight) is tube-fed 2 h before killing, the isolated nuclei show decreased specific l-tryptophan binding (total binding minus non-specific binding using unlabeled l-tryptophan (10 −4 M), at 2000-fold excess) compared with controls. Other fatty acids (oleic, palmitic or linoleic acid at 10 −4 M) when added with excess, unlabeled l-tryptophan (10 −4 M) in vitro to hepatic nuclei revealed some (but less than with valproic acid) decreased specific binding compared with controls. At high doses, valproic acid (80 mg/100 g body weight) appears to decrease tryptophan-induced stimulation of hepatic protein synthesis, probably in a hepatotoxic manner.