MECHANISMS OF FURAN-INDUCED TOXICITY AND CARCINOGENICITY

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DESCRIPTION: Furan is the parent compound for a class of compounds that are toxic or carcinogenic. It is an important industrial compound that is also present in the environment. The widespread occurrence of furan and significant potential for human exposure warrant investigation into the toxicological properties of this compound. Furan, itself, is both toxic and carcinogenic in mice and rats. It has been classified as a nongenotoxic carcinogen. Furan is thought to be activated to a reactive intermediate, cis-2-butene-1,4-dial that alkylates proteins leading to a toxic response. The resulting chronic toxicity stimulates cell replication, which increases the likelihood of tumor production. While cis-2-butene-1,4-dial has been identified as a microsomal metabolite for furan, the precise role of cis-2-butene-1,4-dial in the toxic and carcinogenic properties of furan is not known. The mechanistic role of protein alkylation in furan-mediated toxicity and/or carcinogenicity also remains to be determined. Furthermore, while it is generally accepted that furan is a nongenotoxic carcinogen, there are data that support at least a partial role for a genotoxic mechanism in mice. The role of DNA damage in furan-induced cancer has not been investigated. These knowledge gaps are important problems because they prevent a better understanding of how furan and related compounds induce their toxic and carcinogenic effects. The long range goal is to understand the mechanism by which furan-containing compounds cause their toxic and carcinogenic effects. The objective of this particular application is to determine the role of cis-2-butene-1,4-dial in the toxic and carcinogenic activities of furan. The central hypothesis is that cis-2-butene-1,4-dial is the ultimate reactive species formed during metabolic activation of furan and the reaction of this metabolite with protein and DNA targets initiates the toxic and carcinogenic effects of furan. The PI plans to test the central hypothesis and accomplish the overall objective of this application by pursuing the following specific aims. 1) Characterize the in vivo metabolites of furan, 2) Characterize the protein adducts resulting from furan exposure; 3) Characterize the DNA damage resulting from furan exposure. The proposed studies are expected to yield the following outcomes: first, the PI will determine the importance of cis-2-butene-1,4-dial to the overall in vivo metabolism of furan. Second, the PI will chemically characterize furan protein adducts. These studies will reveal the chemical structure of the ultimate protein alkylating metabolite. Third, the PI will identify the types of DNA damage caused by furan exposure so that they can evaluate the importance of DNA reactions to the adverse effects observed with furan. Collectively, the proposed studies will identify the ultimate reactive species formed during furan metabolism. These studies will set the stage for the determination of the critical events responsible for triggering the toxic and carcinogenic effects of furan. They will also help understand how "nongenotoxic" compounds exert their effects on DNA function.