R. Chang, W. Levin, A. Wood
1982
Citations
4
Influential Citations
31
Citations
Quality indicators
Journal
Cancer research
Abstract
Abstract Dibenzo( a,h )pyrene, [DB( a,h )P], dibenzo( a,i )pyrene [DB( a,i )P], and seven of their benzo-ring derivatives were tested for tumorigenic activity on mouse skin and in newborn mice. In the tumor studies on mouse skin, a single topical application of 50, 200, or 600 nmol of compound was followed 7 days later by twice-weekly applications of the tumor promoter 12- O -tetradecanoylphorbol-13-acetate for 16 or 24 weeks. With the exception of 2,10-difluorodibenzo( a,i )pyrene, all of the compounds had significant tumor-initiating activity at all doses tested. trans -1,2-Dihydroxy-1,2-dihydrodibenzo( a,h )pyrene and trans -3,4-dihydroxy-3,4-dihydrodibenzo( a,i )pyrene, the metabolic precursors of bay-region diol-epoxides, had tumor-initiating activity that was equivalent to their parent hydrocarbons. Saturation of the double bond in the benzo-ring of these dihydrodiols resulted in the formation of tetrahydrodiols whose tumor-initiating activity was not significantly different from that observed with the corresponding dihydrodiols at the 50-nmol dose. The bay-region diol-epoxides of DB( a,h )P and DB( a,i )P, in which the benzylic hydroxyl group and the oxirane oxygen are trans (Isomer 2), induced significantly fewer tumors per mouse than did their dihydrodiol and parent hydrocarbon precursors. In the tumorigenicity study in newborn mice, a total dose of 87.5 nmol of the hydrocarbon divided into three i.p. injections was administered on the first, eighth, and 15th day of life, and tumorigenic activity was determined when the mice were 49 to 54 weeks old. trans -1,2-Dihydroxy-1,2-dihydrodibenzo( a,h )pyrene and trans -3,4-dihydroxy-3,4-dihydrodibenzo( a,i )pyrene induced 3- to 8-fold more pulmonary tumors per mouse and 4- to 5-fold more hepatic tumors per male mouse than the respective parent hydrocarbons. The corresponding tetrahydrodiols had no more than one–eighth of the pulmonary tumorigenic activity of the corresponding dihydrodiol. The bay-region diol-epoxide (Isomer 2) of DB( a,h )P had tumorigenic activity equal to the parent hydrocarbon but significantly less than its dihydrodiol precursor. The bay-region diol-epoxide (Isomer 2) of DB( a,i )P was highly toxic, and only 19% of the mice survived to termination of the study. This diol-epoxide had significantly less tumorigenic activity towards the lung than did either its dihydrodiol precursor or the parent hydrocarbon. Notably, 20% of the surviving mice treated with the diol-epoxide of DB( a,i )P had leukemia at the termination of the study. 2,10-Difluorodi-benzo( a,i )pyrene had no tumorigenic activity in newborn mice at the single dose tested. These results are discussed in relationship to the bay-region theory of polycyclic aromatic hydrocarbon carcinogenicity.