Ammonium chloride inhibits pyruvate oxidation in rat liver mitochondria: a possible cause of fatty liver in Reye's syndrome and urea cycle defects.
1. Earlier studies with liver slices showed that inhibition by NH4+ of the oxidation of palmitate to CO2 was greater than total oxidation, whereas salicylate exerted a stronger inhibitory effect on the latter. We have now investigated the effects of NH4Cl and salicylate on ADP-induced O2 consumption by mitochondria (State 3 rate) respiring on pyruvate, and oxidation of [1-14C]- and [2-14C]-pyruvate to 14CO2. 2. The rate of State 3 respiration was inhibited and plateaued at 45% with 10 mmol/l NH4Cl. 3. Oxidation of [1-14C]pyruvate was not significantly affected by either NH4Cl or salicylate. Oxidation of [2-14C]pyruvate was strongly inhibited and plateaued at 70% with 1 mmol/l NH4Cl (IC50 = 0.125 mmol/l). ADP (1 mmol/l) increased the rate of decarboxylation of [2-14C]pyruvate but the extent of NH4Cl inhibition was not affected. Salicylate had a slight activating effect in the absence or presence of NH4Cl. 4. These results indicate that NH4Cl inhibits the oxidative metabolism of acetyl-CoA in the tricarboxylic acid cycle. Therefore, inhibition of fatty acid oxidation to acetyl-CoA as well as its further oxidative metabolism occurring under hyperammonaemia (> 0.1 mmol-1.49 mmol/l in Reye's syndrome patients) may be one of the causes of fatty acidaemia. 5. The cumulative inhibitory effects of NH4+ and fatty acyl derivatives on mitochondrial oxidative metabolism and production of ATP, as well as the uncoupling effects of salicylate, may contribute to some of the pathophysiology observed in patients with Reye's syndrome, and enzyme defects of the urea cycle.
Maddaiah
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Department of Pediatrics, Nassau County Medical Center, East Meadow, NY.
Kumbar
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D000244:Adenosine Diphosphate / Q000378:metabolism; D000643:Ammonium Chloride / Q000494:pharmacology*; D000818:Animals; D002245:Carbon Dioxide / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005234:Fatty Liver / Q000209:etiology*; D008297:Male; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000378:metabolism; D010084:Oxidation-Reduction / Q000187:drug effects; D010101:Oxygen Consumption / Q000187:drug effects; D011773:Pyruvates / Q000378:metabolism*; D019289:Pyruvic Acid; D051381:Rats; D017207:Rats, Sprague-Dawley; D012202:Reye Syndrome / Q000378:metabolism*; D012459:Salicylates / Q000494:pharmacology; D020156:Salicylic Acid; D014508:Urea / Q000378:metabolism
D011773:Pyruvates; D012459:Salicylates; D000643:Ammonium Chloride; D002245:Carbon Dioxide; D000244:Adenosine Diphosphate; D019289:Pyruvic Acid; D014508:Urea; D020156:Salicylic Acid