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Butadiene monoxide (BM), a mutagen and carcinogen, is the major metabolite of 1,3-butadiene in rats and mice. Because mercapturic acids (N-acetyl-L-cysteine S-conjugates) were expected in vivo metabolites of BM, reference BM-mercapturic acids were prepared by the reaction of racemic BM with N-acetyl-L-cysteine. Four isomers were purified and characterized as diastereomeric pairs of S-(2-hydroxy-3-buten-1-yl)-N-acetyl-L-cysteine (I) and S-(1-hydroxy-3-buten-2-yl)-N-acetyl-L-cysteine (II) based on analyses by 1H NMR, fast atom bombardment mass spectrometry, and high resolution electron impact mass spectrometry. Regioisomers I and II were identified in the urine of rats and mice administered (ip) BM based on GC/MS analyses performed after HPLC fractionation followed by esterification and silylation of the carboxyl and hydroxyl groups, respectively, and comparison of GC retention times with synthetic standards. S-(4-Hydroxy-2-buten-1-yl)-N-acetyl-L-cysteine, a rearrangement product formed during chemical synthesis or storage of both I and II under acidic conditions, was not detected; no other BM metabolites were evident in urine samples using this method. When rats were given BM at a dose of 71.5 to 285 mumol/kg, their urinary excretion of I and II within 8 h of BM administration exhibited linear relationships with the administered BM dose; the total amount of the BM dose excreted as combined I and II averaged 17 +/- 4% (mean +/- SD, n = 15). No metabolites were detected in urine samples collected between 8 and 24 h after BM dosing.(ABSTRACT TRUNCATED AT 250 WORDS)

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Butadiene monoxide, a toxic metabolite of 1,3-butadiene, is a substrate for the human placental glutathione (GSH) S-transferase. The products have been identified as S-(2-hydroxy-3-buten-1-yl)glutathione (I) and S-(1-hydroxy-3-buten-2-yl)glutathione (II). S-(4-hydroxy-2-buten-1-yl)glutathione (III), which was formed chemically, was not detected. 1H NMR analysis of II was consistent with its structure, but spectra of I indicated a 1:1 equilibrium between I and the sulfurane tautomer (IVB) formed by intramolecular displacement of the hydroxyl group by the sulfur atom. The ratio of I to IVB did not change whether the spectrum was obtained at pH 3, 7, or 9 in the presence or absence of LiClO4. Incubations of I at pH 7 or 9 for 5 days at 25 degrees C or for 7 h at 50 degrees C, in the presence or absence of nucleophiles plus LiClO4, did not affect the HPLC profile of I. Storage of I at -20 degrees C for 30 weeks, reflux at pH 7.8 for 5 h in the presence of GSH, or incubations at pH 2 for 5 h at 55 degrees C in the presence of GSH or 2-mercaptoethanol, however, resulted in the conversion of I to III (10-30%). Treatment of I with H2O2 resulted in formation of the corresponding sulfoxide (V) and sulfone (VI), which blocked the formation of III. NMR and chemical reactivity studies of III indicated an initial 1:1 equilibrium between III and the five-membered ring sulfurane (VIIB) formed by intramolecular displacement of the hydroxyl group by the sulfur atom.(ABSTRACT TRUNCATED AT 250 WORDS)