Reduction of tumorigenicity and of dihydrodiol formation by fluorine substitution in the angular rings of dibenzo(a,i)pyrene.
The tumor-initiating activities on mouse skin and in vitro metabolism of dibenzo(a,i)pyrene, 2-fluorodibenzo(a,i)pyrene, 3-fluorodibenzo(a,i)pyrene, and 2, 10-difluorodibenzo(a,i)pyrene were compared. After an initiating dose of 500 micrograms, followed by promotion with tetradecanoylphorbol acetate, dibenzo(a,i)pyrene induced skin tumors in 85% of the mice and caused 5.8 skin tumors/mouse. The corresponding tumorigenic activities for the fluorinated compounds were: 2-fluorodibenzo(a,i)pyrene (85%; 1.7 tumors/mouse); 3-fluorodibenzo(a,i)pyrene (80%; 3.1 tumors/mouse); and 2,10-difluorodibenzo(a,i)pyrene (10%; 0.1 tumors/mouse). After an initiating dose of 100 micrograms, only dibenzo(a,i)pyrene showed significant tumor-initiating activity. 3,4-Dihydro-3,4-dihydroxydibenzo(a,i)pyrene was identified as a metabolite of dibenzo(a,i)pyrene formed by the 9000 X g supernatant from the livers of Aroclor 1254-pretreated rats. Another dihydrodiol was tentatively identified as 1,2-dihydro-1,2-dihydroxydibenzo(a,i)pyrene. The formation of these angular ring dihdrodiols was inhibited in the metabolism of 2-fluorodibenzo(a,i)pyrene and 3-fluorodibenzo(a,i)pyrene. Angular ring dihydrodiols were not detected in the metabolism of 2,10-difluorodibenzo(a,i)pyrene. These results suggest that an angular ring dihydrodiol, 3,4-dihydro-3,4-dihydroxydibenzo(a,i)pyrene, which can form a bay-region dihydrodiol epoxide, may be a proximate carcinogen of dibenzo(a,i)pyrene.
D000818:Animals; D001140:Aroclors / Q000494:pharmacology; D001580:Benzopyrenes / Q000096:biosynthesis* / Q000633:toxicity*; D001711:Biotransformation; D002273:Carcinogens; D020111:Chlorodiphenyl (54% Chlorine); D002851:Chromatography, High Pressure Liquid; D004101:Dihydroxydihydrobenzopyrenes; D005260:Female; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D009374:Neoplasms, Experimental / Q000139:chemically induced / Q000378:metabolism; D051381:Rats; D012878:Skin Neoplasms / Q000139:chemically induced* / Q000378:metabolism
D001140:Aroclors; D001580:Benzopyrenes; D002273:Carcinogens; D004101:Dihydroxydihydrobenzopyrenes; D020111:Chlorodiphenyl (54% Chlorine); C032980:3-fluorobenzo(a,i)pyrene; C032979:2,10-difluorobenzo(a,i)pyrene; C032981:2-fluorobenzo(a,i)pyrene; C021146:dibenzo(a,i)pyrene; C031197:3,4-dihydro-3,4-dihydroxybenzo(a,i)pyrene