Protection against lethal ammonia intoxication: synergism between endogenous ornithine and L-carnitine.
The protective effects of combinations of 5-fluoromethylornithine (5FMOrn), a selective inhibitor of ornithine aminotransferase, and of compounds known to antagonize ammonia toxicity, were studied in acute, lethal ammonia intoxication in mice. Two test conditions were used: (a) Mice were pretreated with 5FMOrn at a dose (5 mumol.kg-1) which partially protects against 13 mmol.kg-1 ammonium acetate. (b) Mice were pretreated with a maximally protective dose of 5FMOrn (0.1 mmol.kg-1), however, 15 mmol.kg-1 ammonium acetate was used for intoxication. Under these conditions treatment with 5FMOrn alone protected only marginally. Under condition (a), administration of L-citrulline, L-carnitine, and L-acetylcarnitine improved the protective effect of 5FMOrn significantly, in an additive manner. N-acetyl-L-glutamate administration was ineffective. Under condition (b), ornithine, arginine and citrulline did not improve the protective effect of 5FMOrn, even when these amino acids were given at doses, which were effective in preventing ammonia toxicity induced with 13 mmol.kg-1 ammonium acetate. The inability to improve the effect of 5FMOrn by these compounds is most probably due to the fact that 5FMOrn and these amino acids enhance urea formation by the same mechanism, namely by increasing the concentration of substrates of the urea cycle. In contrast, L-carnitine and L-acetylcarnitine, which are assumed to stimulate urea production by different mechanisms, or compounds which antagonize ammonia toxicity by a urea cycle-independent mechanism, such as antagonists of the NMDA-type glutamate receptor (MK-801; MDL 100,453), potentiated the effects of 5FMOrn. The principle reason for the observed protective effects of the treatments described in this work seems to be the prevention of accumulation of lethal concentrations of ammonia in the brain. But other effects may also contribute.
Sarhan
S
S
Marion Merrell Dow Research Institute, Strasbourg, France.
Knoedgen
B
B
Seiler
N
N
D000085:Acetates / Q000037:antagonists & inhibitors; D000596:Amino Acids / Q000627:therapeutic use; D000641:Ammonia / Q000037:antagonists & inhibitors* / Q000506:poisoning; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002331:Carnitine / Q000008:administration & dosage / Q000502:physiology / Q000627:therapeutic use*; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005260:Female; D051379:Mice; D009952:Ornithine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000502:physiology / Q000627:therapeutic use*; D011041:Poisoning / Q000517:prevention & control
D000085:Acetates; D000596:Amino Acids; C057405:5-fluoromethylornithine; D000641:Ammonia; D009952:Ornithine; C018824:ammonium acetate; D002331:Carnitine