INHIBITION OF TYROSINE AMINOTRANSFERASE BY BETA-N-OXALYL-L-ALPHA,BETA-DIAMINOPROPIONIC ACID, THE LATHYRUS-SATIVUS NEUROTOXIN

Species differences in susceptibility are a unique feature associated with the neurotoxicity of beta-N-oxalyl-L-alpha,beta-diaminopropionic acid (L-ODAP), the Lathyrus sativus neurotoxin, and the excitotoxic me chanism proposed for its mechanism of toxicity does not account for th is feature. The present study examines whether neurotoxicity of L-ODAP is the result of an interference in the metabolism of any amino acid and if it could form the basis to explain the species differences in s usceptibility. Thus, Wistar rats and BALB/c (white) mice, which are no rmally resistant to L-ODAP, became susceptible to ii following pretrea tment with tyrosine (or phenylalanine), exhibiting typical neurotoxic symptoms. C57BL/6J (black) mice were, however, normally Susceptible to L-ODAP without any pretreatment with tyrosine. Among the various enzy mes associated with tyrosine metabolism examined, the activity of only tyrosine aminotransferase (TAT) was inhibited specifically by L-ODAP. The inhibition was noncompetitive with respect to tyrosine (K-i = 2.0 +/- 0.1 mM) and uncompetitive with respect to alpha-ketoglutarate (K- i = 8.4 +/- 1.5 mM). The inhibition of TAT was also reflected in a mar ked decrease in the rate of oxidation of tyrosine by liver slices, an increase in tyrosine levels of liver, and also a twofold increase in t he dopa and dopamine contents of brain in L-ODAP-injected black mice. The dopa and dopamine contents in the brain of only L-ODAP-injected wh ite mice did not show any change, whereas levels of these compounds we re much higher in tyrosine-pretreated animals. Also, the radioactivity associated with tyrosine, dopa, and dopamine arising from [C-14]tyros ine was twofold higher in both liver and brain of L-ODAP-treated black mice. Thus, a transient increase in tyrosine levels following the inh ibition of hepatic TAT by L-ODAP and its increased availability for th e enhanced synthesis of dopa and dopamine and other likely metabolites (toxic?) resulting therefrom could be the mechanism of neurotoxicity and may even underlie the species differences in susceptibility to thi s neurotoxin.