Synthesis and in vitro characterization of the genotoxic, mutagenic and cell-transforming potential of nitrosylated heme
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GENOTOXICITY AND CARCINOGENICITY
Synthesis and in vitro characterization of the genotoxic, mutagenic and cell‑transforming potential of nitrosylated heme Tina Kostka1,2 · Jörg Fohrer3 · Claudia Guigas4 · Karlis Briviba4 · Nina Seiwert5 · Jörg Fahrer5 · Pablo Steinberg1,4 · Michael T. Empl1 Received: 30 April 2020 / Accepted: 9 July 2020 © The Author(s) 2020
Abstract Data from epidemiological studies suggest that consumption of red and processed meat is a factor contributing to colorectal carcinogenesis. Red meat contains high amounts of heme, which in turn can be converted to its nitrosylated form, NO-heme, when adding nitrite-containing curing salt to meat. NO-heme might contribute to colorectal cancer formation by causing gene mutations and could thereby be responsible for the association of (processed) red meat consumption with intestinal cancer. Up to now, neither in vitro nor in vivo studies characterizing the mutagenic and cell transforming potential of NOheme have been published due to the fact that the pure compound is not readily available. Therefore, in the present study, an already existing synthesis protocol was modified to yield, for the first time, purified NO-heme. Thereafter, newly synthesized NO-heme was chemically characterized and used in various in vitro approaches at dietary concentrations to determine whether it can lead to DNA damage and malignant cell transformation. While NO-heme led to a significant dose-dependent increase in the number of DNA strand breaks in the comet assay and was mutagenic in the HPRT assay, this compound tested negative in the Ames test and failed to induce malignant cell transformation in the BALB/c 3T3 cell transformation assay. Interestingly, the non-nitrosylated heme control showed similar effects, but was additionally able to induce malignant transformation in BALB/c 3T3 murine fibroblasts. Taken together, these results suggest that it is the heme molecule rather than the NO moiety which is involved in driving red meat-associated carcinogenesis. Keywords Nitrosylated heme · Processed red meat · Colon cancer · Genotoxicity · Mutagenicity
Introduction Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00204-020-02846-8) contains supplementary material, which is available to authorized users. * Tina Kostka [email protected]‑hannover.de 1
Institute for Food Toxicology, University of Veterinary Medicine Hannover, Hannover, Germany
2
Present Address: Institute of Food Science and Human Nutrition, Leibniz University Hannover, Hannover, Germany
3
Institute of Organic Chemistry, Leibniz University Hannover, Hannover, Germany
4
Max Rubner-Institut, Federal Research Institute of Nutrition and Food, Karlsruhe, Germany
5
Division of Food Chemistry and Toxicology, Department of Chemistry, Technical University of Kaiserslautern, Kaiserslautern, Germany
Several epidemiological studies suggest that a direct correlation between the incidence of colorectal cancer (CRC) and the consumption of red and processed red
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