Impact of DNA repair on the dose-response of colorectal cancer formation induced by dietary carcinogens.
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.
['Fahrer|Jörg|J|', 'Kaina|Bernd|B|']
D000818:Animals D002273:Carcinogens D015179:Colorectal Neoplasms D018736:DNA Adducts D004249:DNA Damage D004260:DNA Repair D005506:Food Contamination D006801:Humans D008460:Meat
DNA repair Carcinogens MGMT Point of departure Thresholds Genotoxicity AAG Colon cancer Food Heterocyclic amines