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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 NO-heme 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.
Highlights
Several epidemiological studies suggest that a direct correlation between the incidence of colorectal cancer (CRC) and the consumption of red and processed red meat, but not white meat, exists in industrialized nations (English et al 2004; Larsson et al 2005; Norat et al 2005; WCRF/AICR 2007; Vargas and Thompson 2012; Bray et al 2018)
Archives of Toxicology (2020) 94:3911–3927 et al 1993; Shirai et al 1995; Ni et al 2008; Puangsombat et al 2012). Such heat-induced contaminants are rather unlikely to play a prominent role in increasing CRC risk associated with red/processed red meat, as (1) they have been found to occur in all types of heated meat, i.e. in white meat, which is not associated with CRC formation, and (2) their chemical structure often precludes that significant amounts are taken up by colonic cells
These cells were cultured in MEM Eagle’s (EMEM) medium supplemented with 1% (v/v) non-essential amino acids, 2 mM (v/v) l-glutamine, 50 IU ml−1 penicillin G, 50 μg ml−1 streptomycin and 10% (v/v) fetal calf serum (FCS) obtained from Biowest (Nuaille, France)
Summary
Several epidemiological studies suggest that a direct correlation between the incidence of colorectal cancer (CRC) and the consumption of red and processed red meat, but not white meat, exists in industrialized nations (English et al 2004; Larsson et al 2005; Norat et al 2005; WCRF/AICR 2007; Vargas and Thompson 2012; Bray et al 2018). Archives of Toxicology (2020) 94:3911–3927 et al 1993; Shirai et al 1995; Ni et al 2008; Puangsombat et al 2012) Such heat-induced contaminants are rather unlikely to play a prominent role in increasing CRC risk associated with red/processed red meat, as (1) they have been found to occur in all types of heated meat, i.e. in white meat, which is not associated with CRC formation, and (2) their chemical structure often precludes that significant amounts are taken up by colonic cells. In the case of the PAH lead compound benzo[a]pyrene (BaP), a case–control study performed by Helmus et al (2013) showed that the control group was exposed to higher BaP concentrations derived from white meat than the group comprising the actual CRC cases. It has been suggested that mutagenic factors directly arising from red meat itself may play a role in CRC development (Helmus et al 2013)
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