Reactive Metabolites of 1,3-Butadiene: DNA and Hemoglobin Adduct Formation and Potential Roles in Carcinogenicity

Abstract

1,3-Butadiene (BD), a petrochemical widely used in the manufacture of synthetic rubber and plastics, has recently been added to the list of chemicals Known To Be Human Carcinogens based upon epidemiological and mechanistic data indicating a causal relationship between occupational exposure to BD and excess mortality from lymphatic and/or hematopoietic cancers (U.S. Department of Health and Human Services, 2000). Long-term BD inhalation studies in mice and rats have also been associated with genotoxicity and carcinogenicity, with mice being much more sensitive to BD-induced carcinogenicity than rats (Melnick et al, 1990; Owen et al, 1987). Because BD toxicities are believed to be mediated by reactions of BD metabolites with nucleophilic sites on macromolecules, studies in our laboratory have focused on the characterization of potential metabolic pathways of BD bioactivation, in terms of the enzymes involved, the metabolites formed, and the kinetics of the reactions. Bioactivation reactions of several primary and secondary BD metabolites were also examined. In addition, the reactions of butadiene monoxide (BMO), a primary metabolite of BD, with macromolecules were characterized.