Dietary restriction modulated carcinogen-DNA adduct formation and the carcinogen-induced DNA strand breaks

Dietary restriction (DR) alters the activities of hepatic drug metabolizing enzymes and modulates the formation of carcinogen-DNA adducts in carcinogen treated animals. Our previous results showed that a 40% restriction of diet (60% of ad libitum (AL) food consumption) reduced the hepatic metabolic activation of aflatoxin B1 (AFB1) but increased the activation of benzo[a]-pyrene (BaP) in both rats and mice. In this study, the focus was directed toward the levels of carcinogen-DNA adducts formation and the carcinogen-induced DNA strand breaks in mouse kidney and liver DNA. DR significantly inhibited both AFB1-DNA adduct formation and AFB1-induced DNA strand breaks in kidney DNA of mice that received a single dose of [3H]AFB1 (5 mg/kg). The levels of AFB1-DNA adduct formation in mouse kidney DNA correlated well with increased AFB1-induced DNA strand breaks. The correlation between the levels of AFB1-DNA-adducts formed and DNA strand breaks in kidney DNA of DR-mice was less linear than between its AL-counterpart suggesting that other factors, such as different rates of DNA repair, may be involved. In addition, DR enhanced hepatic BaP- and 6-nitrochrysene (6-NC)-DNA adduct formation in the mice treated with BaP and 6-NC, respectively. The formation of the specific BaP-adduct, 10-(N2-deoxyguanosinyl)-7,8,9-trihydroxy-7,8,9,10-tetrahydro-BaP (N2-dG-BaP), in mouse liver was proportional to the dose, and was compatible to the BaP-induced DNA strand breaks affected by DR. The enhancement of the total 6-NC-DNA adduct formation in DR-mouse was also in correlation with the increased 6-NC-induced DNA strand breaks. The activity of mouse liver microsomal nitro-reductase increased by 2-fold in response to DR indicating that the nitroreduction may contribute to the increase of the metabolic activation of 6-NC. Our present results indicate that the effect of DR on the carcinogen activation is dependent upon the DR-modulated carcinogen metabolizing enzyme activities.