Ornithine aminotransferase activity, liver ornithine concentration and acute ammonia intoxication.
5-Fluoromethylornithine (5FMOrn) is a specific inactivator of L-ornithine:2-oxoacid aminotransferase (OAT). Inactivation of OAT causes the enhancement of L-ornithine (Orn) concentrations in all tissues. Intraperitoneal or oral administration of 10-50 mg/kg of 5FMOrn per day to albino mice rendered partial protection against lethal intoxication with 26 mmol/kg of ammonium acetate. The protective effect was maximal around 16 h after 5FMOrn administration, at the time when endogenous Orn concentrations were maximal. At this time protection by 5FMOrn against acute ammonia intoxication was comparable to that observed 1 h after the intraperitoneal administration of 10 mmol/kg of L-arginine. Pretreatment with 5FMOrn prevented the enhancement of excessive urinary excretion of orotic acid by ammonia intoxicated mice, and it enhanced urea formation in the liver. These biochemical effects demonstrate that 5FMOrn shifts Orn into the urea cycle, Orn which normally would be transaminated. Since even long-term treatment of mice with 5FMOrn did not reveal toxic effects, this compound may be considered for the treatment of certain conditional deficiencies of Orn or arginine.
Seiler
N
N
Merrell Dow Research Institute, Strasbourg, France.
Grauffel
C
C
Daune
G
G
Gerhart
F
F
D000085:Acetates / Q000633:toxicity*; D000284:Administration, Oral; D000641:Ammonia / Q000032:analysis / Q000097:blood; D000818:Animals; D001120:Arginine / Q000494:pharmacology; D003404:Creatinine / Q000652:urine; D000518:Eflornithine / Q000031:analogs & derivatives / Q000494:pharmacology; D005260:Female; D007274:Injections, Intraperitoneal; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D051379:Mice; D009952:Ornithine / Q000097:blood / Q000378:metabolism*; D009953:Ornithine-Oxo-Acid Transaminase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009963:Orotic Acid / Q000652:urine; D000637:Transaminases / Q000378:metabolism*; D014508:Urea / Q000032:analysis
D000085:Acetates; D009963:Orotic Acid; D000641:Ammonia; D014508:Urea; D001120:Arginine; D003404:Creatinine; D009952:Ornithine; D000637:Transaminases; D009953:Ornithine-Oxo-Acid Transaminase; C018824:ammonium acetate; D000518:Eflornithine