Colorectal cancer (CRC) is one of the most frequently diagnosed
cancers, which is causally linked to dietary habits, notably the intake of processed and red meat. Processed and red meat contain dietary
carcinogens, including heterocyclic aromatic
amines (HCAs) and N-
nitroso compounds (NOC). NOC are agents that induce various N-methylated
DNA adducts and
O6-methylguanine (O6-MeG), which are removed by base excision repair (BER) and O6-methylguanine-DNA
methyltransferase (MGMT), respectively. HCAs such as the highly mutagenic 2-amino-1-methyl-6-phenylimidazo[4,5-
b]pyridine (
PhIP) cause bulky
DNA adducts, which are removed from
DNA by nucleotide excision repair (NER). Both O6-MeG and HCA-induced
DNA adducts are linked to the occurrence of KRAS and APC mutations in
colorectal tumors of rodents and humans, thereby driving CRC initiation and progression. In this review, we focus on DNA repair pathways removing DNA lesions induced by NOC and HCA and assess their role in protecting against mutagenicity and carcinogenicity in the large intestine. We further discuss the impact of DNA repair on the dose-response relationship in colorectal
carcinogenesis in view of recent studies, demonstrating the existence of 'no effect' point of departures (PoDs), i.e. thresholds for genotoxicity and carcinogenicity. The available data support the threshold concept for NOC with DNA repair being causally involved.