Effects of ornithine aminotransferase inactivation by 5-fluoromethylornithine in rats following portacaval anastomosis.
5-Fluoromethylornithine (5FMOrn) is a selective inactivator of ornithine aminotransferase. Administration of this compound to rodents causes a prominent increase of tissue ornithine concentrations, and prevents the neurological consequences of acute ammonia intoxication. However, long-term treatment with 5FMOrn of rats with portacaval shunts did not result in decreased circulating ammonia concentrations, nor did it prevent other pathologic manifestations of shunting. The sensitivity to ammonia intoxication of rats with portacaval shunts was also unaffected by pretreatment with 5FMOrn, although liver ornithine concentrations were significantly elevated; specific activities of urea cycle enzymes were slightly higher in portacaval shunted compared to sham-operated controls following 5-FMOrn treatment. Administration of 5FMOrn dramatically elevated urinary excretion of several amino acids in rats with portacaval shunts, but not in sham-operated animals, suggesting that the reabsorption of amino acids from the glomerular filtrate may be impaired in shunted rats. These results suggest that, in contrast to acute hyperammonemic syndromes, 5-FMOrn may be of limited therapeutic value in chronic hyperammonemia syndromes in which there is significant portal-systemic shunting.
Neuroscience Research Unit, Hôpital Saint-Luc (Univ. of Montreal), Qué., Canada.
G
G
Therrien
S
S
Sarhan
B
B
Knödgen
R F
RF
Butterworth
N
N
Seiler
D000596:Amino Acids / Q000378:metabolism; D000641:Ammonia / Q000097:blood* / Q000506:poisoning; D000818:Animals; D001835:Body Weight; D001921:Brain / Q000378:metabolism; D008099:Liver / Q000502:physiology; D008297:Male; D009952:Ornithine / Q000031:analogs & derivatives* / Q000494:pharmacology; D009953:Ornithine-Oxo-Acid Transaminase / Q000037:antagonists & inhibitors*; D011167:Portacaval Shunt, Surgical; D051381:Rats; D017207:Rats, Sprague-Dawley
D000596:Amino Acids; C057405:5-fluoromethylornithine; D000641:Ammonia; D009952:Ornithine; D009953:Ornithine-Oxo-Acid Transaminase