The ‘neurotoxicity’ of l-2,4-diaminobutyric acid

Abstract

The neurolathyrbgen L-2, 4-diaminobutyric acid is concentrated by liver, and liver damage can yield neurotoxicity; thus the neurotoxicity caused by this compound may be due to liver damage followed by secondary brain damage. The intraperitoneal administration of toxic doses of L-2, 4-diaminobutyric acid to rats resulted in hyperirritability, tremors and convulsions in 12-20 hr. and increased the concentration of ammonia of blood and brain slightly and the concentration of glutamine of brain 2-to-3-fold. By contrast, toxic doses of L-homoarginine, L-lysine, L-leucine and ammonium acetate caused by dysponea, extreme prostration, and in some cases coma in 15-30 min., and increased the concentration of ammonia of blood significantly and the concentration of glutamine of brain slightly. These results indicate that L-2, 4-diaminobutyric acid caused a chronic ammonia toxicity, whereas the other amino acids and ammonium acetate resulted in an acute ammonia toxicity. Liver slices from L-2, 4-diaminobutyric acid-treated animals and normal liver slices preincubated with L-2, 4-diaminobutyric acid utilized ammonia and formed urea at a lower rate than control slices from normal rats. L-2, 4-Diaminobutyric acid inhibited competitively orni-thine carbamoyltransferase of rat liver homogenates, thus demonstrating that this reaction is a primary site of toxicity for this neurolathyrogen. Although we were unable to show marked elevations of blood ammonia concentration after treatment with L-2, 4-diaminobutyric acid, these results are interpreted to mean that ammonia utilization (urea synthesis) in liver is inhibited by L-2, 4-diaminobutyric acid and that at least part of the neurotoxicity is due to a prolonged slight increase in body ammonia concentration.