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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
1R01ES010577-01
Application #
6166077
Study Section
Chemical Pathology Study Section (CPA)
Program Officer
Thompson, Claudia L
Project Start
2000-08-17
Project End
2004-07-31
Budget Start
2000-08-17
Budget End
2001-07-31
Support Year
1
Fiscal Year
2000
Total Cost
$259,875
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Public Health & Prev Medicine
Type
Schools of Public Health
DUNS #
168559177
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
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
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
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
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
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

Showing the most recent 10 out of 17 publications