Inhibition of ornithine aminotransferase by 5-fluoromethylornithine: protection against acute thioacetamide intoxication by elevated tissue ornithine levels.
5-Fluoromethylornithine (5FMOrn) is a selective inactivator of ornithine aminotransferase. Its administration causes a dramatic increase of ornithine concentrations in all tissues. Treatment of mice with 20 mg.kg-1 5FMOrn shortly before or after a lethal dose (600 mg.kg-1, intraperitoneally) of thioacetamide (TAA), followed by a second dose 24 hr later, prevented death of 60% of the mice. Pathologic symptoms of TAA intoxication (liver haemorrhage, elevation of amino acids in blood and tissues, diminution of liver spermidine and spermine concentrations, elevation of the activity of liver enzymes in the plasma) were significantly ameliorated by the treatment. The liver protective action of 5FMOrn is related to the elevation of ornithine concentration, as appears from the fact that other, less selective inactivators of ornithine aminotransferase, also produced some protection against acute intoxication with TAA, but not a structurally related compound with no effect on this enzyme.
Seiler
N
N
Marion Merrell Dow Research Institute, Strasbourg, France.
Sarhan
S
S
Knödgen
B
B
D000596:Amino Acids / Q000097:blood; D000641:Ammonia / Q000097:blood; D000818:Animals; D015317:Biogenic Polyamines / Q000097:blood; D056486:Chemical and Drug Induced Liver Injury; D006470:Hemorrhage / Q000139:chemically induced / Q000517:prevention & control; D008107:Liver Diseases / Q000517:prevention & control; D008297:Male; D051379:Mice; D009952:Ornithine / Q000031:analogs & derivatives* / Q000494:pharmacology; D009953:Ornithine-Oxo-Acid Transaminase / Q000037:antagonists & inhibitors*; D010865:Pilot Projects; D011041:Poisoning / Q000097:blood / Q000517:prevention & control; D013853:Thioacetamide / Q000506:poisoning*
D000596:Amino Acids; D015317:Biogenic Polyamines; D013853:Thioacetamide; C057405:5-fluoromethylornithine; D000641:Ammonia; D009952:Ornithine; D009953:Ornithine-Oxo-Acid Transaminase