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Drug Metabolism and Disposition Fast Forward
First published on July 8, 2005; DOI: 10.1124/dmd.105.004432

0090-9556/05/3310-1453-1458$20.00
DMD 33:1453-1458, 2005

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GLUTATHIONE TRAPPING TO MEASURE MICROSOMAL OXIDATION OF FURAN TO CIS-2-BUTENE-1,4-DIAL

Lisa A. Peterson, Meredith E. Cummings, Choua C. Vu, and Brock A. Matter

Division of Environmental Health Sciences (L.A.P., M.E.C., C.C.V.) and The Cancer Center (L.A.P., M.E.C., C.C.V., B.A.M.), University of Minnesota, Minneapolis, Minnesota

Furan is a liver carcinogen and toxicant. Furan is oxidized to the reactive dialdehyde, cis-2-butene-1,4-dial, by microsomal enzymes. This reactive metabolite readily reacts with glutathione nonenzymatically to form conjugates. A high-performance liquid chromatography-electrochemical method for the detection of cis-2-butene-1,4-dial-glutathione (GSH) conjugates in microsomal preparations was developed to measure the extent of furan metabolism to cis-2-butene-1,4-dial in vitro. Previously unobserved mono-GSH reaction products of cis-2-butene-1,4-dial were detected in addition to the already characterized bis-GSH conjugates. Chemical characterization of these compounds indicated that the {alpha}-amino group of glutathione had reacted with cis-2-butene-1,4-dial to form a thiol-substituted pyrrole adduct. The analytical method was used to estimate the extent of furan oxidation in rat liver microsomes from untreated or acetone-pretreated F344 rats as well as in human P450 2E1 Supersomes. Our results confirm that cytochrome P450 2E1 can catalyze the oxidation of furan to cis-2-butene-1,4-dial. However, the data are also consistent with the involvement of other P450 enzymes in the oxidation of furan in untreated animals. This assay will be a valuable tool to explore tissue and species differences in rates of furan oxidation.

Address correspondence to: Dr. Lisa Peterson, The Cancer Center, University of Minnesota, Mayo Mail Code 806, 420 Delaware St. S.E., Minneapolis, MN 55455. E-mail: peter431{at}umn.edu






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