Furan is an important industrial compound that is also present in the environment. It is both hepatoxic and carcinogenic in mice and rats. Based on these results and the potential for human exposure, furan has been listed as a possible human carcinogen. The mechanism of tumor induction by furan is unknown. The available experimental evidence suggests that both nongenotoxic and genotoxic mechanisms contribute to the overall carcinogenic outcome. It is clear that the toxicity and carcinogenicity is initiated by cytochrome P450 catalyzed oxidation of furan to an a,(3-unsaturated dialdehyde, c/s-2-butene-1,4-dial. However, it is possible that further metabolism of c/s-2-butene-1,4-dial generates other reactive metabolites that contribute to the toxic effects of furan. Our long-range goal is to determine the mechanism of furan-induced carcino- genesis in rodents so that we can develop effective tools to determine if humans exposed to furan are sus- ceptible to its toxicological properties. The objective of this application is to determine if furan is a genotoxic carcinogen in vivo and to better define the metabolic processes that lead to its activation or detoxification. The central hypothesis is that both cytotoxic and genotoxic pathways contribute to the overall carcinogenic effects of furan with the involvement of multiple metabolic pathways. We formulated this hypothesis on the basis of strong preliminary data that suggest that the oxidation of furan to c/s-2-butene-1,4-dial initiates the process. While this reactive metabolite can alkylate both DNA and protein in vitro, it is also likely to be further metabolized to other toxic compounds in vivo. We plan to test our hypothesis by pursuing the following specific aims: 1) Determine the mutagenic activity of furan in Big Blue rodents;2) Characterize the in vivo metabolic pathways of furan;3) Compare the pathways of furan metabolism in human and rodent hepatocytes and determine the enzymes involved in each pathway. Collectively, these specific aims will provide important data for testing mechanisms of furan toxicity and tumorigenesis. With this information, we can develop appropriate model systems to assess the role of genotoxicity and cytotoxicity in the carcinogenic properties of furan. In addition, these studies will aid in the development of appropriate biomarkers (urinary metabolites, protein and/or DNA adducts) that can be used to determine if these toxicologically important reactions are occurring in humans exposed to furan.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
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Special Emphasis Panel (ZRG1-ONC-P (02))
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Reinlib, Leslie J
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University of Minnesota Twin Cities
Public Health & Prev Medicine
Schools of Public Health
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Grill, Alex E; Schmitt, Thaddeus; Gates, Leah A et al. (2015) Abundant Rodent Furan-Derived Urinary Metabolites Are Associated with Tobacco Smoke Exposure in Humans. Chem Res Toxicol 28:1508-16
Gates, Leah A; Phillips, Martin B; Matter, Brock A et al. (2014) Comparative metabolism of furan in rodent and human cryopreserved hepatocytes. Drug Metab Dispos 42:1132-6
Terrell, Ashley N; Huynh, Mailee; Grill, Alex E et al. (2014) Mutagenicity of furan in female Big Blue B6C3F1 mice. Mutat Res Genet Toxicol Environ Mutagen 770:46-54
Phillips, Martin B; Sullivan, Mathilde M; Villalta, Peter W et al. (2014) Covalent modification of cytochrome c by reactive metabolites of furan. Chem Res Toxicol 27:129-35
Peterson, Lisa A (2013) Reactive metabolites in the biotransformation of molecules containing a furan ring. Chem Res Toxicol 26:6-25
Gates, Leah A; Lu, Ding; Peterson, Lisa A (2012) Trapping of cis-2-butene-1,4-dial to measure furan metabolism in human liver microsomes by cytochrome P450 enzymes. Drug Metab Dispos 40:596-601
Peterson, Lisa A; Phillips, Martin B; Lu, Ding et al. (2011) Polyamines are traps for reactive intermediates in furan metabolism. Chem Res Toxicol 24:1924-36
Lu, Ding; Peterson, Lisa A (2010) Identification of furan metabolites derived from cysteine-cis-2-butene-1,4-dial-lysine cross-links. Chem Res Toxicol 23:142-51
Lu, Ding; Sullivan, Mathilde M; Phillips, Martin B et al. (2009) Degraded protein adducts of cis-2-butene-1,4-dial are urinary and hepatocyte metabolites of furan. Chem Res Toxicol 22:997-1007
Peterson, Lisa A (2006) Electrophilic intermediates produced by bioactivation of furan. Drug Metab Rev 38:615-26

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