METABOLIC PATHWAYS OF 1-BUTYL [3-C-13]ACRYLATE - IDENTIFICATION OF URINARY METABOLITES IN RAT USING NUCLEAR-MAGNETIC-RESONANCE AND MASS-SPECTROSCOPY

1-Butyl acrylate, an industrial monomer, is rapidly metabolized by car boxylesterase-catalyzed hydrolysis to acrylic acid and 1-butanol. Acry lic acid enters the intermediary metabolism and is efficiently degrade d to carbon dioxide as the metabolic end product. To obtain a virtuall y complete metabolic pattern, rats were dosed by a single intraperiton eal dose of 1 mmol/kg 1-butyl [3-C-13]acrylate. The urine was then ana lyzed by a one-dimensional H-1-detected and two-dimensional H-1-C-13 s hift-correlated heteronuclear multiple-quantum NMR experiment. In this experiment, three urinary metabolites, namely, 3-hydroxypropanoic aci d, N-acetyl-S-(2-carboxyethyl)cysteine, and N-acetyl-S-(2-carboxyethyl )cysteine sulfoxide, were identified by comparing their H-1 and C-13 c hemical shifts with those of authentic standards. In another experimen t, to enhance minor metabolic pathways, rats were dosed with 0.25 mmol /kg of a carboxylesterase inhibitor, tri-o-tolyl phoshpate, prior to 0 .5 mmol/kg butyl [3-C-13]acrylate. Under these conditions, N-acetyl-S- (2-carboxyethyl) cysteine, N-acetyl-S-[2-(butoxycarbonyl) ethyl] cyste ine, and N-acetyl-S-(2-carboxyethyl)cysteine sulfoxide were found in u rine. No metabolites which would arise from a possible metabolic activ ation of 1-butyl acrylate to 1-butyl oxiranecarboxylate and its subseq uent hydrolysis or glutathione conjugation were found. It is estimated that any metabolite amounting to more than 1% of the dose should be d etected under these conditions. To study the routes by which BA enters the intermediary metabolism, incorporation of the label into urinary carboxylic acids was followed by GC/MS. Significant enrichment was fou nd in 3-hydroxypropanoic acid and citric and isocitric acid but not in lactic acid. These results confirm that the main metabolic pathway of butyl acrylate is its carboxylesterase-catalyzed hydrolysis. The resu lting acrylic acid enters the intermediary metabolism via a minor path way of propanoic acid catabolism and tricarboxylate cycle. Glutathione conjugation leading to mercapturic acids is a minor pathway of butyl acrylate metabolism.