Influences of complex organic mixtures on tumor-initiating activity, DNA binding and adducts of benzo[a]pyrene.
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 demonstrated 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 fractions 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/micrograms 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-deoxy-guanosine 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.
Springer
D L
DL
Pacific Northwest Laboratory, Richland, WA 99352.
Mann
D B
DB
Dankovic
D A
DA
Thomas
B L
BL
Wright
C W
CW
Mahlum
D D
DD
D015123:7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide / Q000378:metabolism; D000818:Animals; D001564:Benzo(a)pyrene / Q000378:metabolism / Q000633:toxicity*; D001711:Biotransformation; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D002851:Chromatography, High Pressure Liquid; D003031:Coal / Q000633:toxicity*; D003043:Cocarcinogenesis; D004249:DNA Damage; D004357:Drug Synergism; D005260:Female; D006358:Hot Temperature; D051379:Mice; D012878:Skin Neoplasms / Q000139:chemically induced*
D003031:Coal; D001564:Benzo(a)pyrene; D015123:7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide