L-carnitine protection in ammonia intoxication. Effect of aminocarnitine on carnitine-dependent metabolism and acute ammonia toxicity.
Intraperitoneal administration of L-carnitine (16 mmol/kg) was reported by O'Connor et al. (FEBS Lett 166: 331-334, 1984) to fully protect mice from ammonium acetate given at a dose that kills 100% of untreated controls. Other investigators either have failed to observe protection by L-carnitine or have attributed the increased survival to a nonspecific "osmoprotective effect" of quaternary ammonium compounds. In the present studies we have confirmed the protective effect of L-carnitine in acute ammonia intoxication and have shown that D-carnitine and deoxycarnitine, close structural analogs of L-carnitine, are without protective effect. Although D-carnitine and deoxycarnitine do not support L-carnitine-dependent metabolisms, they are transported into tissues and their solutions are osmotically identical to those of L-carnitine; lack of protection by D-carnitine and deoxycarnitine suggests that metabolic rather than nonspecific osmotic effects account for L-carnitine-mediated protection. Further supporting the importance of L-carnitine-dependent metabolisms, we found that mice exhibited increased sensitivity to ammonium acetate when pretreated with DL-aminocarnitine, acetyl-DL-aminocarnitine or palmitoyl-DL-aminocarnitine, potent inhibitors of the carnitine acyltransferases. Interestingly, intraperitoneal injection of hyperosmotic solutions of sodium chloride or sucrose did afford significant protection against subsequently administered ammonium acetate. This phenomenon, which may be due to interference with ammonium acetate uptake from the peritoneal cavity or to reduction of cerebral edema by increased plasma osmolarity, apparently does not play a major role in L-carnitine-mediated protection since, as noted, hyperosmotic D-carnitine and deoxycarnitine solutions were not protective.
Ohtsuka
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Department of Biochemistry, Cornell University Medical College, New York, NY 10021.
Griffith
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D000085:Acetates / Q000008:administration & dosage / Q000633:toxicity; D000641:Ammonia / Q000493:pharmacokinetics / Q000506:poisoning*; D000818:Animals; D001622:Betaine / Q000031:analogs & derivatives / Q000494:pharmacology; D002210:Caprylates / Q000008:administration & dosage / Q000494:pharmacology; D002331:Carnitine / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000627:therapeutic use*; D002333:Carnitine Acyltransferases / Q000037:antagonists & inhibitors; D004305:Dose-Response Relationship, Drug; D007274:Injections, Intraperitoneal; D007279:Injections, Subcutaneous; D008297:Male; D051379:Mice; D010529:Peritoneal Cavity / Q000502:physiology; D011041:Poisoning / Q000378:metabolism / Q000517:prevention & control; D012965:Sodium Chloride / Q000494:pharmacology / Q000627:therapeutic use; D013395:Sucrose / Q000494:pharmacology / Q000627:therapeutic use; D013997:Time Factors
D000085:Acetates; D002210:Caprylates; D001622:Betaine; D012965:Sodium Chloride; D013395:Sucrose; D000641:Ammonia; C045761:emeriamine; D002333:Carnitine Acyltransferases; C031492:octanoic acid; C018824:ammonium acetate; D002331:Carnitine