Influences of complex organic mixtures on tumor-initiating activity, DNA binding and adducts of benzo[a]pyrene

• Published in: Carcinogenesis (New York) 1989-01, Vol.10 (1), p.131-137
• Main Authors: Springer, D.L., Mann, D.B., Dankovic, D.A., Thomas, B.L., Wright, C.W., Mahlum, D.D.
• Format: Article
• Language: English
• Subjects: 7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide - metabolism; Animals; Benzo(a)pyrene - metabolism; Benzo(a)pyrene - toxicity; Biological and medical sciences; Biotransformation; Carcinogenesis, carcinogens and anticarcinogens; Chemical agents; Chemical Phenomena; Chemistry, Physical; Chromatography, High Pressure Liquid; Coal - toxicity; Cocarcinogenesis; DNA Damage; Drug Synergism; Female; Hot Temperature; Medical sciences; Mice; Skin Neoplasms - chemically induced; Tumors
• ISSN: 0143-3334; 1460-2180
• DOI: 10.1093/carcin/10.1.131

Co-incubation of benzo[a]pyrene (BaP) and coal-derived complex organic mixtures has been shown to decrease the metabolism and mutagenic activity of BaP. Because of these influences, five mixtures were co-administered dermally to mice to initiate tumor development. Results from these studies dex.nonstrated that BaP tumor-initiating activity was decreased substantially by four of the five mixtures. When one of the mixtures was separated into chemical class fractions, the polycyclic aromatic hydrocarbon (PAH) and nitrogen-containing polycyclic aromatic compound fractions were the most effective, and the aliphatic and hydroxy-PAH fractious were the least effective as inhibitors of BaP-induced tumor initiation. Binding of [3H]BaP to epidermal DNA under conditions identical to those used for tumor initiation was decreased by co-administration of all five mixtures. Calculations of the number of tumors produced/μg BaP bound to DNA demonstrated that co-administration of this carcinogen with the mixtures consistently increased the effectiveness of the bound BaP at producing tumors by approximately a factor of 2. The HPLC radioactivity profiles of enzyme-hydrolyzed, adducted DNA indicated that, in the presence of the mixtures, the predominant adducts were derived from BaP-diol epoxide (BPDE); however, the mixtures decreased the ratios of the anti-BPDE-deoxyguanosine to syn-BPDE-deoxyguanosine adducts. These data indicate that the prevailing influences of the mixtures (i.e. decreased DNA binding and adduct shifts) were similar to those observed with other bioassays following co-administration of binary mixtures. Furthermore, the data demonstrate that both DNA binding and adduct profiles are important in determining the contribution of a known carcinogen to tumor initiation by complex organic mixtures.