1191 EFFECTS OF SALICYLATE ON OXIDATION OF OCTANOATE AND PALMITOYL COENZYME A IN RAT LIVER MITOCHONDRIA: IMPLICATIONS FOR REYE'S SYNDROME

Abstract

We studied the effect of salicylate (SA) on fatty acid (FA) oxidation in isolated rat liver mitochondria (mito), in order to investigate a possible link between the evidence for an association of aspirin ingestion with Reye's Syndrome and perturbed fat metabolism in this disease. Mito were incubated for FA oxidation with either 0.1 mM 14C-octanoate (C8 or 0.1 mM 14C-palmitoyl CoA (C16 CoA) plus 0.5 mM carnitine,as substrate. The rate of oxidation was followed as the amount of 14CO2 formed. C8 was chosen to represent short chain FA which are permeable to mito and which therefore can be activated to CoA esters by an ATP-dependent reaction in the matrix prior to B-oxidation. C16CoA was representative of long chain FA, which are impermeable to mito and which must be activated to CoA esters in the cytosol prior to carnitine-dependent transport into the matrix for B-oxidation. SA inhibited C4 oxidation in a concentration dependent manner with maximum inhibition (71.3±3%) at 2.5 mM SA. In contrast, C16 CoA oxidation was increased 49±13% by 2.5 mM SA. These effects were traced to SA's uncoupling activity, which stimulates uncoupled respiration and lowers the matrix ATP concentration. Thus at modest concentrations, SA selectively inhibits the oxidation of FA that are activated to CoA esters in the mito matrix, but stimulates the oxidation of FA that have been activated in the cytosol. This suggests a possible contributory role for aspirin in the development of Reye's Syndrome, since an excess of short chain FA has been proposed to be important in the pathogenesis of this illness. (NIH NS 14936).