Effect of cancer chemopreventive agents on microsome-mediated DNA adduction of the breast carcinogen dibenzo[a,l]pyrene.
Due to the large and expanding number of potential cancer chemopreventive agents, there is an increasing need for short term tests to study the efficacy and mechanisms of these agents. In this study, we have employed a microsome-mediated test system to study the effect of several suspected chemopreventive agents on the DNA adduct formation capacity of the potent mammary carcinogen, dibenzo[a,l]pyrene (DBP). Bioactivation of DBP by Aroclor 1254-induced rat liver microsomes in the presence of calf thymus DNA (300 microg/ml) resulted in the formation of one major and six other prominent DNA adducts (324 adducts/10(7) nucleotides). These adducts were previously determined to be deoxyadenosine (dA) and deoxyanosine (dG)-derivatives of both anti- and syn-DBP-11,12-diol-13,14-epoxides (DBPDE). Intervention with ellagic acid, chlorophyllin, benzyl isocyanate (BIC), oltipraz or genistein (150 microM) strongly diminished DBP-DNA adduction by > or = 75%. Linoleic acid, curcumin and butylated hydroxytoluene (BHT) also significantly inhibited DBP DNA adduction (26-46%) while N-acetylcysteine (NAC) had no effect. Moreover, nonenzymatic studies with anti- and syn-DBPDE isomers revealed that chlorophyllin, ellagic acid, BIC and BHT may be inhibiting DBP-DNA adduction in an enzymatic-independent manner since these agents diminished DBPDE-DNA adduction by 30-75%. Genistein, oltipraz and curcumin did not diminish DBPDE-DNA adduction and therefore most likely require the presence of the microsomal subcellular fraction to inhibit DBP-DNA adduction.
Smith
W A
WA
Graduate Center for Toxicology, University of Kentucky Medical Center, Lexington 40536-0305, USA.
Arif
J M
JM
Gupta
R C
RC
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001580:Benzopyrenes / Q000378:metabolism* / Q000633:toxicity; D001711:Biotransformation; D002273:Carcinogens / Q000378:metabolism* / Q000633:toxicity; D018890:Chemoprevention; D018736:DNA Adducts / Q000187:drug effects*; D005260:Female; D008325:Mammary Neoplasms, Experimental / Q000139:chemically induced / Q000188:drug therapy; D008862:Microsomes, Liver / Q000187:drug effects*; D051381:Rats
D000970:Antineoplastic Agents; D001580:Benzopyrenes; D002273:Carcinogens; D018736:DNA Adducts; C041517:dibenzo(a,l)pyrene