The 'neurotoxicity' of L-2,4-diaminobutyric acid.
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.
D000613:Aminobutyrates / Q000494:pharmacology*; D000641:Ammonia / Q000097:blood; D000818:Animals; D001120:Arginine / Q000494:pharmacology; D001224:Aspartic Acid / Q000032:analysis; D001786:Blood Glucose; D001923:Brain Chemistry; D002645:Chickens; D002852:Chromatography, Ion Exchange; D005971:Glutamates / Q000032:analysis; D005973:Glutamine / Q000032:analysis; D066298:In Vitro Techniques; D007930:Leucine / Q000494:pharmacology; D008099:Liver / Q000378:metabolism; D008239:Lysine / Q000494:pharmacology; D008297:Male; D009952:Ornithine / Q000494:pharmacology; D009954:Ornithine Carbamoyltransferase / Q000378:metabolism; D011188:Potassium / Q000032:analysis; D000644:Quaternary Ammonium Compounds / Q000494:pharmacology; D051381:Rats; D012964:Sodium / Q000032:analysis; D013053:Spectrophotometry; D013997:Time Factors; D014508:Urea / Q000032:analysis / Q000096:biosynthesis; D014556:Urine / Q000187:drug effects
D000613:Aminobutyrates; D001786:Blood Glucose; D005971:Glutamates; D000644:Quaternary Ammonium Compounds; D005973:Glutamine; D001224:Aspartic Acid; D000641:Ammonia; D014508:Urea; D001120:Arginine; D012964:Sodium; D009952:Ornithine; D009954:Ornithine Carbamoyltransferase; D007930:Leucine; D008239:Lysine; D011188:Potassium