METABOLISM AND DISTRIBUTION OF [2,3-C-14]ACROLEIN IN SPRAGUE-DAWLEY RATS - II - IDENTIFICATION OF URINARY AND FECAL METABOLITES

The metabolites of [2,3-C-14]acrolein in the urine and feces of Spragu e-Dawley rats were identified after either intravenous administration in saline at 2.5 mg/kg or oral administration by gavage as an aqueous solution as either single or multiple doses at 2.5 mg/kg or as a singl e dose of 15 mg/kg. Selected urine and feces samples were pooled by se x and collection interval and profiled by combinations of reverse-phas e, anion-exchange, cation-exchange, and ion-exclusion high-performance liquid chromatography (HPLC). Feces were also profiled by size-exclus ion chromatography. Metabolites were identified by comparison with wel l-characterized standards by HPLC and by mass spectrometry. The urinar y metabolites were identified as oxalic acid, malonic acid, N-acetyl-S -2-carboxy-2-hydroxyethylcysteine, N-acetyl-S-2-hydroxypropylcysteine, N-acetyl-S-2-carboxyethylcysteine, and 3-hydroxypropionic acid. The f ecal radioactivity from the oral dose groups was partitioned into meth anol-soluble, water-soluble, and insoluble radioactivity, some of whic h could be liberated by dilute acid hydrolysis. HPLC analysis of these extracts revealed no discrete metabolites. Size-exclusion chromatogra phy indicated a molecular weight range of 2,000 to 20,000 Da for the r adioactivity, which was unaffected by hydrolysis at reflux with 6 M ac id or base. This radioactivity was thought to be a homopolymer of acro lein, which was apparently formed in the gastrointestinal tract. The p athways of acrolein metabolism were epoxidation followed by conjugatio n with glutathione, Michael addition of water followed by oxidative de gradation, and glutathione addition to the double bond either followin g or preceding oxidation or reduction of the aldehyde. The glutathione adducts were further metabolized to the mercapturic acids. (C) 1998 S ociety of Toxicology.