Neurotoxicity of ammonia and fatty acids: differential inhibition of mitochondrial dehydrogenases by ammonia and fatty acyl coenzyme A derivatives.
In several metabolic encephalopathies, hyperammonemia and organic acidemia are consistently found. Ammonia and fatty acids (FAs) are neurotoxic: previous workers have shown that ammonia and FAs can act singly, in combination, or synergistically, in inducing coma in experimental animals. However, the biochemical mechanisms underlying the neurotoxicity of ammonia and FAs have not been fully elucidated. FAs are normally converted to their corresponding CoA derivatives (CoAs) once they enter cells and it is known that these fatty acyl CoAs can alter intermediary metabolism. The present study was initiated to determine the effects of ammonia and fatty acyl CoAs on brain mitochondrial dehydrogenases. At a pathophysiological level (2 mM), ammonia is a potent inhibitor of brain mitochondrial alpha-ketoglutarate dehydrogenase complex (KGDHC). Only at toxicological levels (10-20 mM) does ammonia inhibit brain mitochondrial NAD(+)- and NADP(+)- linked isocitrate dehydrogenase (NAD-ICDH, NADP-ICDH), and NAD(+)-linked malate dehydrogenase (MDH) and liver mitochondrial NAD-ICDH. Butyryl- (BCoA), octanoyl- (OCoA), and palmitoyl (PCoA) CoA were potent inhibitors of brain mitochondrial KGDHC, with IC50 values of 11, 20, and 25 microM, respectively; moreover, the inhibitory effect of fatty acyl CoAs and ammonia were additive. At levels of 250 microM or higher, both OCoA (IC50 = 1.15 mM) and PCoA (IC50 = 470 microM) inhibit brain mitochondrial NADP-ICDH; only at higher levels (0.5-1 mM) does BCoA inhibit this enzyme (by 30-45%). Much less sensitive than KGDHC and NADP-ICDH, brain mitochondrial NAD-ICDH is only inhibited by 1 mM BCoA, OCoA, and PCoA by 22%, 35%, and 44%, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
Lai
J C
JC
Department of Biochemistry, Cornell University Medical College, New York, NY 10021.
Cooper
A J
AJ
D000214:Acyl Coenzyme A / Q000494:pharmacology*; D000641:Ammonia / Q000494:pharmacology*; D000704:Analysis of Variance; D000818:Animals; D001921:Brain / Q000201:enzymology*; D007521:Isocitrate Dehydrogenase / Q000037:antagonists & inhibitors*; D007655:Ketoglutarate Dehydrogenase Complex / Q000037:antagonists & inhibitors*; D007700:Kinetics; D008297:Male; D008928:Mitochondria / Q000201:enzymology*; D008930:Mitochondria, Liver / Q000201:enzymology*; D009498:Neurotoxins / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains
D000214:Acyl Coenzyme A; D009498:Neurotoxins; D000641:Ammonia; D007521:Isocitrate Dehydrogenase; D007655:Ketoglutarate Dehydrogenase Complex