Red meat-derived, endogenously formed nitroso compounds: potential to malignantly transform human colon cell cells and underlying modes of action

• Applicant: Professor Dr. Pablo Steinberg
• Subject Area: Public Health, Healthcare Research, Social and Occupational Medicine
• Term: from 2015 to 2018
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 271358822

In industrialized nations consumption of red meat correlates with colorectal cancer incidence. It has been shown that red but not white meat dose-dependently induces the endogenous formation of nitroso compounds such as nitrosyl heme and nitrosothiols in the human gut. Since red meat contains much more heme than white meat, a direct relationship between heme intake and the endogenous formation of nitroso compounds has been suggested. In this context, it has been postulated that endogenously formed nitroso compounds may lead to the formation of the alkylating agent diazoacetate, which in turn gives rise to O6-carboxymethylguanine adducts, results in specific gene mutations and in the end induces colorectal cancer. The aims of the project are: 1) to determine if on the one hand nitroso compounds formed by incubating human faeces with nitrate/nitrite and heme and on the other hand nitrosyl heme formed in the culture medium by the reaction of NO with heme are able to malignantly transform human colon epithelial cells; 2) to determine whether the incubation of human colon epithelial cells with endogenously formed nitroso compounds and nitrosyl heme results in the formation of O6-carboxymethylguanine adducts in the treated cells; 3) to determine whether Ki-ras, APC and/or p53 gene mutations are present in the malignantly transformed human colon epithelial cells; 4) to determine whether the simultaneous administration of nitrite and heme to rats is accompanied by the formation of O6-carboxymethylguanine adducts, the induction of Ki-ras, APC and/or p53 gene mutations and an enhanced formation of preneoplastic and neoplastic lesions in the colon and/or rectum of the experimental animals. The planned experiments will show for the first time whether the above-mentioned pathway (nitrate/nitrite + heme, endogenously formed nitroso compounds, O6-carboxymethylguanine adducts, Ki-ras, APC and/or p53 gene mutations) leads to the malignant transformation of human colon epithelial cells. The animal experiment will show whether the above-mentioned chain of events does in fact occur in vivo.

• DFG Programme: Research Grants