Toxic effect of valproic acid on tryptophan binding to rat hepatic nuclei.
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.
Sidransky
H
H
Department of Pathology, George Washington University Medical Center, Washington, DC 20037, USA.
Verney
E
E
D000818:Animals; D000927:Anticonvulsants / Q000008:administration & dosage / Q000633:toxicity*; D001665:Binding Sites; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000633:toxicity*; D005260:Female; D019787:Linoleic Acid; D008041:Linoleic Acids / Q000633:toxicity; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D051379:Mice; D008807:Mice, Inbred BALB C; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D009685:Nuclear Envelope / Q000187:drug effects / Q000378:metabolism; D019301:Oleic Acid; D009829:Oleic Acids / Q000633:toxicity; D019308:Palmitic Acid; D010169:Palmitic Acids / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D014316:Tritium / Q000378:metabolism; D014364:Tryptophan / Q000008:administration & dosage / Q000378:metabolism* / Q000494:pharmacology; D014635:Valproic Acid / Q000008:administration & dosage / Q000633:toxicity*
D000927:Anticonvulsants; D004791:Enzyme Inhibitors; D008041:Linoleic Acids; D009829:Oleic Acids; D010169:Palmitic Acids; D014316:Tritium; D019301:Oleic Acid; D019308:Palmitic Acid; D014635:Valproic Acid; D014364:Tryptophan; D019787:Linoleic Acid