Furan in food: a dietary risk factor for human cholangiocarcinoma? Characterization of functional changes an protein adducts in the hepatobliliary tract of rats exposed to turan

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In a recent investigation, the U.S. Food and Drug Administration (FDA) identified the chemical furan in a variety of food items that undergo heat treatment. Furan is a potent hepatotoxicant and liver carcinogen in rodents. Chronic administration of furan to rats at doses as low as 2 mg/kg b.w. results in very high incidences of cholangiocarcinoma. Although data on human intake of furan are limited, it appears that there is a relatively narrow margin between human exposure and doses which cause liver tumors in rodents, suggesting that the presence of furan in food may present a potential risk to human health. However, the presently available data on furan toxicity is insufficient to perform a risk assessment and more research regarding the mechanism of furan carcinogenicity is needed. In an in vivo study using 14C-labeled furan, covalent binding of furan or its reactive metabolite cis-2-butene-1,4-dial to DNA could not be established. In contrast, 80% of the radioactivity present in livers was found to be associated with proteins. It has been suggested that chronic inflammation and enhanced biliary cell proliferation in response to furan cytotoxicity, mediated through binding of cis-2-butene-1,4-dial to critical target proteins, is likely to play a key role in furan carcinogenicity. The aim of the proposed work is to identify target proteins of furan reactive intermediates by employing state-of-the-art proteomics methods involving administration of 14C-labeled furan to rats, separation of unmodified and furan-adducted proteins present in liver by two-dimensional gel electrophoresis, autoradiography, and identification of proteins by modern MS techniques, and to characterize the cellular and functional consequences associated with protein damage by analyzing markers of hepatobiliary injury, histopathological alterations and cell proliferation, and changes in protein expression. With the knowledge to be gained in this project, particularly in relation to the dose-response relationships, decisions can be made as to whether furan levels in food need to be controlled.