Dietary variables associated with DNA N7-methylguanine levels and O6-alkylguanine DNA-alkyltransferase activity in human colorectal mucosa

Abstract

Components of human diets may influence the incidence of colorectal adenomas, by modifying exposure or susceptibility to DNA-damaging alkylating agents. To examine this hypothesis, a food frequency questionnaire was used to assess the diet of patients recruited for a case-referent study where biopsies of normal colorectal mucosa were collected during colonoscopy and subsequently analysed for DNA N7-methylguanine (N7-MeG) levels, as an indicator of exposure, and activity of the DNA repair protein O 6 -alkylguanine DNA-alkyltransferase (MGMT), as an indicator of potential susceptibility. Cases with histologically proven colorectal adenomas (n 5 38) were compared with referents (n 5 35) free of gastrointestinal neoplasia. The case group consumed significantly more red meat (4.5 versus 3.4 servings/week, P < 0.05), processed meats, (4.7 versus 3.2 servings/week, P < 0.05) and % food energy as fat (34.9 versus 30.7%, P < 0.001). N7-MeG [mean: 95% confidence interval (CI)] levels were significantly lower in the group that consumed the highest proportion of dietary fibre/1000 kcal in comparison with the group with the lowest intake (0.61; 0.35-0.86 versus 1.88; 0.88-2.64 mmol/mol dG, P < 0.05). N7-MeG levels were also inversely associated with folate consumption (P < 0.05). MGMT activity (mean; 95% CI) was significantly higher in the group with the lowest consumption of vegetables than in the group with the greatest vegetable consumption (7.02; 5.70-8.33 versus 4.93; 3.95-5.91 fmol/mg DNA, P < 0.05). Our results are consistent with the hypothesis that dietary factors may modify exposure or susceptibility, respectively, to DNA damage by alkylating agents.

Inhibition by Resistant Starch of Red Meat–Induced Promutagenic Adducts in Mouse Colon

“…There are no previous reports of the effect of dietary protein on the alkyl-induced DNA adduct O 6 MeG. In a case study examining biopsies of normal colorectal mucosa, red meat was found to be a risk factor in the formation of N 7 -methylguanine (N 7 -MeG) but that adduct is not oncogenic (41). A randomized crossover trial comparing high red meat, vegetarian, and high red meat/high fiber diets showed marked increases of the O 6 -carboxymethylguanine (O 6 CMG) in exfoliated colon cells when healthy volunteers consumed a high red meat diet (9); however, exfoliated cells might acquire new adducts in the lumen with more direct exposure to protein fermentation products.…”

Folate and cancer: how DNA damage, repair and methylation impact on colon carcinogenesis

“…Here, individuals in the lowest tertile of total dietary folate intake (<170 μg/1,000 kcal per day) had significantly lower NER repair capacity compared with those in the upper tertile (>225 μg/1,000 kcal per day). MGMT activity, measured in normal human colon biopsies is inversely linked to vegetable consumption, whereas low dietary folate intake is specifically associated with high levels of alkylation damage (Billson et al 2009). Whereas folate deficiency appears to affect DNA repair detrimentally, it is unclear whether increasing folate intake can improve repair.…”

DNA Damage Protection and Induction of Repair by Dietary Phytochemicals and Cancer Prevention: What Do We Know?

“…Some dietary agents, such as genistein and epigallocatechin-3-gallate showed the ability to reactivate some methylation-silenced genes in cancer cells like MGMT due to a direct inhibition of DNA methyltransferase (Fang et al, 2005;Fang et al, 2003). Recently, Billson et al, (2009), demonstrated that a high vegetable intake in humans decreases MGMT activity in normal colorectal mucosa. To understand the real role of dietary agents on chemotherapy when in combination with alkylating drugs more studies are need.…”