Perturbation of subcellular acyl‐CoA metabolism by methoxy acetic acid

Toxicity of ethylene glycol monomethyl ether is mediated by 2‐methoxy acetic acid (MAA, 3‐oxabutanoic acid). Impact of MAA on enzymes critical to normal lipid metabolism (acyl‐CoA synthetase (ACS), acyl‐CoA hydrolase (ACH), carnitine acyltransferase (CAT), diacylglycerol acyltransferase (DGAT), glycine N‐acyltransferases, and UDP‐glucuronosyltransferases) is evaluated with subcellular rat liver fractions. For ACS, MAA was compared with physiologic butanoic acid; mitochondrial ACS activity was 60% greater (376.9 nmol/min/mg vs 234.7) with MAA. For other assays, synthetic MAA‐CoA and butanoyl‐CoA were used. Peroxisomal ACH hydrolyzed MAA‐CoA at 22% the rate of butanoyl‐CoA (0.26 vs 1.16 nmol/min/mg). Reactivity of MAA‐CoA with mitochondrial and peroxisomal CAT was 20% and 28% that of control. MAA‐CoA was more reactive with UDP‐glucuronosyltransferases compared to butanoyl‐CoA (13.5 vs 8.90 nmol/min/mg). Decreased hydrolysis and membrane transport of MAA‐CoA, compared with its facile synthesis, may sequester CoA in subcellular compartments. Decreased glycine conjugation of MAA‐CoA suggests that MAA is not effectively eliminated by this route; thus MAA‐CoA may accumulate in detrimental amounts and possibly interfere with other mitochondrial metabolic reactions. (Supported by Oakland University REF.)