Natural and process-related carcinogens in food: Macromolecular adducts in animal models and human blood and tissue samples.
Most genotoxic carcinogens are metabolically activated to electrophilic intermediates that may form DNA and protein adducts. DNA adducts in target tissues are directly involved in the mechanism underlying the carcinogenicity. And adducts in general are biomarkers for the internal exposure to the corresponding reactive metabolites. These adducts can be analysed as nucleoside and amino acid adducts after digestion of the macromolecules. Liquid chromatography coupled with tandem mass spectrometry, with stable-isotope-labelled internal standards, is a promising approach due to its high reliability regarding the identification and accurate quantification of the analytes. We developed such analytical methods for (i) DNA and protein adducts of two phytochemicals occurring in food plants, methyleugenol and 1-methoxy-3-indolylmethyl glucosinolate (MIM-GL), (ii) DNA adducts of 5-hydroxymethyfurfural and furfuryl alcohol, which are formed from acid or heat-treated carbohydrates, and (iii) DNA adducts of 1-methylpyrene, a carcinogenic polycyclic aromatic hydrocarbon found in many foods. All these compound require bioactivation by sulfotransferases (SULTs) for adduct formation. First, we investigated these adducts (dose-response relationship, time course, persistence, tissue distribution, adduct levels in blood proteins versus levels of DNA adducts in target organs) in conventional animal models and mouse lines humanized for relevant SULT forms. Subsequently, we searched for the adducts in human blood and tissue specimens. DNA adducts of methyleugenol were detected in surgical liver samples from 150 (out of 151) subjects. They were associated with SULT1A1 expression, implying that host factors in addition to methyleugenol uptake were important for the adduct formation. DNA adducts of methyleugenol as well as furfuryl alcohol were also detected in all 10 human lung samples examined. High levels of serum albumin and haemoglobin adducts of MIM-GL were found after a broccoli-rich diet. Lower adduct levels were found in many subjects even before intervention. The findings show that it is now feasible to use adducts as biomarkers of the individual exposure and bioactivation/inactivation. The next step – started now in our laboratory – will address associations between adduct levels and cancer risks.
Glatt, H.; Meinl, W.; Engst, W.; Schumacher, F.; Sachse, B.; Herrmann, K.; Barknowitz, G.; Bernau, M.; Bendadani, C.; Wiesner, M.; Schreiner, M.; Tremmel, R.; Bub, A.; Zanger, U.; Monien, B. 2015. Natural and process-related carcinogens in food: Macromolecular adducts in animal models and human blood and tissue samples. Toxicology Letters 238 (2), Supplement p 33.