Induction of (omega-1)-oxidation of monocarboxylic acids by acetylsalicylic acid.
Monocarboxylic acids may be oxidized at the omega- and (omega-1)- positions to form dicarboxylic acids (DCAs) and (omega-1)-hydroxy- or (omega-1)-oxoacids. The significance of this pathway under normal conditions is unknown, but DCAs and (omega-1)-hydroxyacids are prominent features of disease states. The stimulation of this pathway has been linked to induction of fatty acid-binding protein and peroxisomal proliferation. In this study, we examined the effect of acetylsalicylic acid (ASA) on (omega-1)-oxidation. (Omega-1)-oxidation was assessed in subcellular fractions of rat liver. Rats were fed a normal diet or an ASA-supplemented diet. Products were identified by gas chromatography-mass spectrometry (GC-MS) and by comparison with the properties of authentic synthetic standards. Doses of ASA that produced relatively low serum concentrations (12-24 mg/dl) resulted in as much as a 20-fold increase in the capacity for (omega-1)-oxidation of medium (C12-C15) and long chain (C16-C20) monocarboxylic acids. Normal rat liver oxidizes monocarboxylic acids to (omega-1)-oxoacids, while liver from ASA-treated rats converts these substrates to (omega-1)-oxodicarboxylic acids and (omega-1)-oxoacids. The formation of oxoacids and oxodicarboxylic acids may be due to different enzymes. The formation of oxodicarboxylic acids appears to be more labile than the formation of oxoacids. These two processes also are differentially induced by ASA and have different substrate specificities. These results demonstrate that ASA is a potent stimulant of (omega-1)-oxidation and induces the formation of products that can be shortened in peroxisomes to key metabolic intermediates.
Kundu
R K
RK
Department of Pediatrics, Pritzker Medical School, University of Chicago, IL 60637.
Getz
G S
GS
Tonsgard
J H
JH
D000818:Animals; D001241:Aspirin / Q000494:pharmacology*; D005231:Fatty Acids, Unsaturated / Q000378:metabolism*; D007651:Keto Acids / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D010084:Oxidation-Reduction; D051381:Rats; D017207:Rats, Sprague-Dawley; D013347:Subcellular Fractions / Q000737:chemistry
D005231:Fatty Acids, Unsaturated; D007651:Keto Acids; D001241:Aspirin