TOXIC EFFECT OF VALPROIC ACID ON TRYPTOPHAN BINDING TO RAT HEPATIC NUCLEI

This study evaluated whether valproic acid, a branched-chain fatty aci d which has been used in the treatment of seizures, would influence th e binding of L-tryptophan to rat hepatic nuclei. Previous studies have indicated that binding of L-tryptophan to hepatic nuclear envelope pr otein was saturable, stereospecific, and of high affinity. In this stu dy, we investigated whether valproic acid, which under certain conditi ons is heptatoxic, would influence L-tryptophan binding to rat hepatic nuclei as assayed by in vitro L-(5-H-3)tryptophan binding. Our result s indicate that the addition of valproic acid to hepatic nuclei or nuc lear envelopes in vitro has little influence on their L-(5-H-3)tryptop han binding. On the other hand, when valproic acid (80 mg/100 g body w eight) is tube-fed 2 h before killing, the isolated nuclei show decrea sed specific L-tryptophan binding (total binding minus non-specific bi nding using unlabeled L-tryptophan (10(-4) M), at 2000-fold excess) co mpared with controls. Other fatty acids (oleic, palmitic or linoleic a cid 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 valp roic acid) decreased specific binding compared with controls. At high doses, valproic acid (80 mg/100 g body weight) appears to decrease try ptophan-induced stimulation of hepatic protein synthesis, probably in a hepatotoxic manner.