The mechanism of inhibition of β-oxidation by aspirin metabolites in skin fibroblasts from Reye’s syndrome patients and controls

Abstract

The effects of aspirin metabolites on beta-oxidation were studied in skin fibroblasts from eight typical Reye's syndrome (RS) patients and controls. RS patients' cells did not differ from controls in rates of palmitate oxidation or in the three component activities of the mitochondrial trifunctional enzyme (MTE), indicating no inherited beta-oxidation defect. Aspirin metabolites salicylate, hydroxyhippurate and gentisate, but not aspirin, directly inhibited palmitate oxidation in control and RS cells. RS cells were significantly more sensitive to inhibition than controls at 0.5 to 5 mM salicylate. Inhibition was concentration-dependent and reversible. Inhibition did not occur in fibroblasts lacking activity of the long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) activity of MTE. Salicylate was therefore inhibiting beta-oxidation at this step. Hydroxyhippurate and salicylate reversibly inhibited HAD activities in extracts of control and RS cells. Studies with pure short-chain HAD and LCHAD (MTE) showed hydroxyhippurate and salicylate were competitive inhibitors of the former but mixed (not competitive) inhibitors of the latter. Both compounds inhibited the combined, three-step, MTE reaction measured in the physiological direction. We conclude that (1) salicylate and hydroxyhippurate decrease beta-oxidation in intact cells by reversible inhibition of LCHAD activity of the MTE, and (2) beta-oxidation in RS cells is inherently more sensitive to inhibition by low concentrations of salicylate than controls.

Skeletal muscle inflammation is not responsible for the rapid impairment in adiponectin response with high-fat feeding in rats

“…We speculated that ASA might decrease mitochondrial content (oxidative capacity) of the muscle, rendering it incapable of responding to a stimulus of oxidation above basal levels. Very limited evidence in patients with Reyes Syndrome suggests that aspirin may inhibit palmitate oxidation in skin fibroblasts from both control and diseased patients (14). To this end, we measured two markers of mitochondrial content (citrate synthase, ␤-HAD protein content), but data did not show any decrease in their content in soleus muscle from ASA-supplemented animals (data not shown).…”

“…One milliliter of the aqueous phase was quantified by liquid scintillation counting to determine the amount of 14 Clabeled oxidation intermediates resulting from isotopic fixation. Muscle lipids were redissolved in 100 l of 2:1 chloroform-methanol, spotted onto an oven-dried silica gel plate (Fisher Scientific Canada, Mississauga, ON, Canada), and placed into a sealed tank containing 60:40:3, heptane:isopropyl-ether: acetic acid for 50 min.…”

Mitochondrial Associated Yeast Flocculation -The Effect of Acetylsalicylic Acid

“…According to Glasgow and co-workers 13 , salicylate, the primary metabolite of ASA, inhibits ␤-oxidation of medium and long-chain fatty acids in rodent liver mitochondria but not peroxisomes. This may be ascribed to ASA metabolites having structural similarities to the acyl-portions of the substrate and product of the 3-hydroxyacyl-CoA dehydrogenase activity of the ␤-oxidation pathway.…”

“…It is proposed that 3-OH oxylipins are produced by incomplete ␤-oxidation probably in the mitochondria of fungi 12 and then released and deposited on cell/ascospore surfaces 22 . It has been reported that ASA inhibits ␤-oxidation in mitochondria and thus 3-OH oxylipins synthesis 7,13 . Thus, literature suggests that mitochondrial function and yeast flocculation is interrelated 11,21,33,35 .…”

Co‐ingestion of aspirin and acetaminophen promoting fulminant liver failure: A critical review of Reye syndrome in the current perspective at the dawn of the 21st century

“…16 In animal models, the release of cytokines, such as TNFɑ, from macrophages is known to have a wide range of effects including inhibition of β-oxidation of long chain fatty acids in hepatocytes. 17,18 This aspect leads to increased levels of plasma ammonia and free fatty acids, which causes mitochondrial damage and hepatic fatty infiltration.…”