Tumor-initiating activity and metabolism of polymethylated phenanthrenes.
The tumor-initiating activity of several polymethylated phenanthrenes was determined in mouse skin. Among the compounds assayed were 1,4-, 1,9-, 2,7-, 3,6-, 4,5-, 4,9-, and 4,10-dimethylphenanthrene. Only the 1,4- and 4,10-dimethylphenanthrenes were active as tumor initiators. Initiating doses of 300 micrograms and 1.0 mg of 1,4-dimethylphenanthrene after promotion with tetradecanoylphorbol acetate induced 80 and 100% incidences of skin tumors in mice, respectively, 4,10-Dimethylphenanthrene assayed under identical conditions induced skin tumors in 35 and 55% of the mice. The in vitro metabolism of 1,4-, 3,6-, 4,9-, and 4,10-dimethylphenanthrene was studied by incubation of the compounds with the 9000 x g supernatant from the livers of Aroclor-pretreated rats. The major dihydrodiol metabolite of both 1,4- and 4,10-dimethylphenanthrene was the 7,8-dihydrodiol, the requisite precursor for the formation of bay-region dihydrodiol-epoxides. Dihydrodiols were not observed among the metabolites of 4,9-dimethylphenanthrene. In the case of 3,6-dimethyphenanthrene, the major diol metabolite formed in vitro was the 9,10-dihydrodiol. These results support previously proposed structural requirements which favor the carcinogenic activity of methylated polynuclear aromatic hydrocarbons. These studies indicate that tumorigenic activity of methylated phenanthrenes requires inhibition of dihydrodiol formation at the K-region (9,10-positions) in addition to a bay-region methyl group and a free peri position, both adjacent to an unsubstituted angular ring.
D000818:Animals; D002273:Carcinogens / Q000378:metabolism*; D005260:Female; D008297:Male; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D009374:Neoplasms, Experimental / Q000473:pathology; D010616:Phenanthrenes / Q000138:chemical synthesis / Q000378:metabolism*; D051381:Rats; D011916:Rats, Inbred F344; D012878:Skin Neoplasms / Q000139:chemically induced* / Q000473:pathology; D013329:Structure-Activity Relationship
D002273:Carcinogens; D010616:Phenanthrenes; C035676:1,4-dimethylphenanthrene; C035677:4,10-dimethylphenanthrene