Inhibition of liver microsome-mediated mutagenesis, metabolism and DNA-binding of benzo[a]pyrene and benzo[a]pyrene 7,8-dihydrodiol in the rat following glucose administration.
Aroclor 1254-induced rat liver microsomes prepared from control and glucose-treated rats (30% glucose in drinking water 48 h prior to sacrifice) were used in studies of benzo[a]pyrene (BaP) and BaP 7,8-dihydrodiol (BaP 7,8-DHD)-induced mutagenesis in Salmonella typhimurium TA100. Microsome-dependent metabolism and metabolite binding of BaP and BaP 7,8-DHD to calf thymus DNA was also investigated. BaP-induced mutagenesis in TA100 was inhibited 27% and BaP 7,8-DHD-induced mutagenesis was inhibited 55% by microsomes from glucose-treated rats. [3H]BaP and [3H]BaP 7,8-DHD metabolite binding to DNA was inhibited 17% and 20%, respectively. High performance liquid chromatographic (hplc) analysis of enzyme-hydrolyzed DNA yielded 7R and 7S-diol epoxide-1 deoxyguanosine (BPDE-1:dG) adducts and BPDE-2:dG adducts of [3H]BaP and [3H]BaP 7,8-DHD. These adducts were inhibited 38% and 50%, respectively, by microsomes from glucose-treated rats. Hplc analysis of organosoluble metabolites of [3H]BaP and [3H]BaP 7,8-DHD showed an inhibition of metabolism of 28% and 50%, respectively, by microsomes from glucose-treated rats. The inhibition of metabolism correlated with the effect of glucose treatment on inhibition of BaP and BaP 7,8-DHD-induced mutagenesis and adduct formation. These results suggest that the mechanism by which glucose produces its effects on mutagenesis, DNA-binding and adduct formation is by an inhibition of microsome-mediated metabolism of BaP and BaP 7,8-DHD.
Vance
R E
RE
Department of Physiology and Pharmacology, Loma Linda University, School of Medicine, CA 92350.
Teel
R W
RW
Strother
A
A
D015123:7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide / Q000378:metabolism; D000818:Animals; D001564:Benzo(a)pyrene / Q000378:metabolism* / Q000633:toxicity; D004247:DNA / Q000378:metabolism*; D018736:DNA Adducts; D003864:Depression, Chemical; D004101:Dihydroxydihydrobenzopyrenes / Q000378:metabolism* / Q000633:toxicity; D005947:Glucose / Q000494:pharmacology*; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000502:physiology*; D009152:Mutagenicity Tests; D009154:Mutation; D051381:Rats; D011919:Rats, Inbred Strains
D018736:DNA Adducts; D004101:Dihydroxydihydrobenzopyrenes; C043931:benzo(a)pyrene-7,8-dihydrodiol-9,10-epoxide-DNA; C056612:benzo(a)pyrene-DNA adduct; C017228:benzo(a)pyrene 7,8-dihydrodiol; D001564:Benzo(a)pyrene; D015123:7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide; D004247:DNA; D005947:Glucose