The neurolathyrogen
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. 1. The intraperitoneal administration of toxic doses of
l-2,4-diaminobutyric acid to rats resulted in hyperirritability,
tremors and convulsions in 12-20hr. and increased the concentration of
ammonia of blood and brain slightly and the concentration of
glutamine of brain two- to three-fold. By contrast, toxic doses of l-
homoarginine,
l-lysine,
l-leucine and
ammonium acetate caused dyspnoea, extreme prostration, and in some cases
coma in 15-30min., 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. 2. 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. 3.
l-2,4-Diaminobutyric acid inhibited competitively
ornithine 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.