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Metabolic activation and inactivation of food carcinogens 5-hydroxymethylfurfural and furfuryl alcohol in humans, mice and rats
Project
Project code: DFG
Contract period: 01.12.2014
- 30.09.2015
Purpose of research: Basic research
5-Hydroxymethylfurfural (HMF) and furfuryl alcohol (FFA) are moderately potent rodent carcinogens present in many foodstuffs, in which they are formed by heat- and acid-catalyzed reactions from carbohydrates. The margins between the doses that induce tumors in animal experiments and the estimated daily human intake amounts are alarmingly small. Sulfotransferases (SULTs) convert HMF and FFA to mutagenic esters. If the carcinogenicity were due to such a genotoxic mechanism, the low margins of exposure would indicate a high risk in humans. Moreover, due to considerable differences in SULT expression between species, humans may be more sensitive to HMF and FFA than rodents. I propose to study conjugation of HMF and FFA by individual SULTs of different species and compare capacities of toxifying sulfo conjugation and detoxifying oxidative elimination in individual tissues of humans, mice and rats. In addition, FFA activation will be studied monitoring tissue distributions of macromolecular methylfuran adducts in transgenic mouse lines expressing human SULTs (1A1/1A2) and in knock-out lines lacking endogenous Sults (1a1 and 1d1). Methylfuran adducts of DNA and blood proteins will be tested for their applicability as human biomarkers of internal exposure. The data about species-related differences in metabolism in vitro and adduct formation in vivo will support the assessment of carcinogenic risks resulting from human dietary exposure to HMF and FFA.
The basic goal of the project was to elucidate 5-Hydroxymethylfurfural (HMF) and furfuryl alcohol (FFA) bioactivation and detoxification in mice and rats, the animal models of carcinogenicity studies, and in humans. In all three species the bioactivation of HMF and FFA to reactive sulfate esters is mainly catalyzed by sulfotransferase (SULT)1A1. HMF sulfo conjugation and oxidative detoxification was studied in individual tissues (liver, kidney, lung and colon) of humans, mice and rats in vitro. The results indicated that HMF sulfo conjugation was most substantial in the liver of female mice, the target tissue for HMF-induced neoplastic effects, and that humans may be less sensitive regarding HMF sulfo conjugation compared to the rodent models. The genotoxicity of HMF and FFA was studied in mice following i.p. injection of 100 mg/kg body weight. The FFA-related DNA adduct N2-((furan-2-yl)methyl)-2'-deoxyguanosine (N2-MFdG) was detected in DNA samples of different tissues. Interestingly, the co-treatment of FFA-exposed mice with ethanol increased levels of N2-MFdG, demonstrating an indirect genotoxic effect of ethanol resulting from competitive inhibition of alcohol dehydrogenases (ADHs) and aldehyde dehydrogenases (ALDHs). An equimolar dose of HMF but also direct administration of 100 mg of the reactive metabolite 5-sulfoxymethylfurfural (SMF)/kg body weight did not lead to formation of detectable adduct levels in mice. Also, HMF-related DNA adducts were not detected in human tissue samples, whereas DNA adducts of FFA such as N2-MFdG were detectable in tissue samples of human lung and to a lesser extend in liver, kidney and colon. The results indicated that the genotoxicity of HMF is minute in comparison to that of FFA.
Section overview
Subjects
- Toxicology