title: Synthesis and characterization of N-acetyl-L-cysteine S-conjugates of butadiene monoxide and their detection and quantitation in urine of rats and mice given butadiene monoxide.
abstract: 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)
authors.affiliation: Department of Comparative Biosciences, University of Wisconsin, Madison 53706, USA.
authors.forename: A A
authors.initials: AA
authors.lastname: Elfarra
authors.forename: J E
authors.initials: JE
authors.lastname: Sharer
authors.forename: R J
authors.initials: RJ
authors.lastname: Duescher
mesh_terms: D000111:Acetylcysteine / Q000378:metabolism*; D000818:Animals; D002273:Carcinogens / Q000378:metabolism*; D004852:Epoxy Compounds / Q000378:metabolism*; D008297:Male; D051379:Mice; D009153:Mutagens / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D002273:Carcinogens; D004852:Epoxy Compounds; D009153:Mutagens; C024370:3,4-epoxy-1-butene; D000111:Acetylcysteine