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.
Department of Toxicology, University Medical Center Mainz, Obere Zahlbacher Strasse 67, D-55131 Mainz, Germany. Electronic address: fahrer@uni-mainz.de.
Jörg
J
Fahrer
Department of Toxicology, University Medical Center Mainz, Obere Zahlbacher Strasse 67, D-55131 Mainz, Germany. Electronic address: kaina@uni-mainz.de.
Bernd
B
Kaina
D000818:Animals; D002273:Carcinogens / Q000633:toxicity*; D015179:Colorectal Neoplasms / Q000209:etiology* / Q000235:genetics*; D018736:DNA Adducts / Q000235:genetics; D004249:DNA Damage; D004260:DNA Repair; D005506:Food Contamination / Q000032:analysis*; D006801:Humans; D008460:Meat / Q000032:analysis
D002273:Carcinogens; D018736:DNA Adducts
AAG; Carcinogens; Colon cancer; DNA repair; Food; Genotoxicity; Heterocyclic amines; MGMT; Point of departure; Thresholds