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.
Chou
M W
MW
National Center for Toxicological Research, Jefferson, AR 72079, USA.
Chen
W
W
Mikhailova
M V
MV
Nichols
J
J
Weis
C
C
Jackson
C D
CD
Hart
R W
RW
Chung
K T
KT
D016604:Aflatoxin B1 / Q000378:metabolism* / Q000633:toxicity; D000818:Animals; D001564:Benzo(a)pyrene / Q000378:metabolism / Q000633:toxicity; D001711:Biotransformation; D002273:Carcinogens / Q000378:metabolism* / Q000633:toxicity; D002911:Chrysenes / Q000378:metabolism / Q000633:toxicity; D018736:DNA Adducts / Q000378:metabolism*; D004249:DNA Damage; D005508:Food Deprivation / Q000502:physiology*; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008862:Microsomes, Liver / Q000201:enzymology; D009153:Mutagens / Q000378:metabolism / Q000633:toxicity; D009601:Nitroreductases / Q000378:metabolism; D051381:Rats
D002273:Carcinogens; D002911:Chrysenes; D018736:DNA Adducts; D009153:Mutagens; D001564:Benzo(a)pyrene; C035986:6-nitrochrysene; D016604:Aflatoxin B1; C037214:1-nitropyrene reductase; D009601:Nitroreductases