Tumorigenic Activity of 3-Methylcholanthrene Metabolites on Mouse Skin and in Newborn Mice

Abstract

3-Methylcholanthrene and eight of its metabolites were tested for tumorigenic activity in two tumor models. In the tumorigenicity study on mouse skin, a single topical application of 3 to 30 nmol of compound was followed 7 days later by twice weekly applications of the tumor promotor 12-O-tetradecanoylphorbol-13-acetate for 30 weeks. Comparisons of the percentage of mice with tumors and the average number of tumors per mouse indicated that 3-methylcholanthrene, 2-hydroxy-3-methylcholanthrene, 3-methylcholanthrene-2-one, and a 1,9,10-trihydroxy-9,10-dihydro-3-methylcholanthrene diastereomer were approximately equipotent as tumor initiators. 1-Hydroxy-3-methylcholanthrene had approximately one-fourth the tumor-initiating activity of the most active compounds, and 3-methylcholanthrene-1-one and trans-11,12-dihydroxy-11,12-dihydro-3-methylcholanthrene had no significant tumorigenic activity at the doses tested. In the tumorigenicity study in newborn mice, increasing amounts of the compounds were injected i.p. on the 1st, 8th, and 15th days of life to give a total dose of 21 or 49 nmol. The experiment was terminated when the animals were 35 to 39 weeks old. With respect to pulmonary tumors, 1,9,10-trihydroxy-9,10-dihydro-3-methylcholanthrene was the most tumorigenic compound tested at both doses. 3-Methylcholanthrene and 3-methylcholanthrene-2-one were the next most active compounds, and they had approximately one-half to one-third of the activity of 1,9,10-trihydroxy-9,10-dihydro-3-methylcholanthrene when the data were expressed as pulmonary tumors per mouse. 2-Hydroxy-3-methylcholanthrene was slightly less active than were 3-methylcholanthrene and 3-methylcholanthrene-2-one. 1-Hydroxy-3-methylcholanthrene had marginal tumorigenic activity. 3-Methylcholanthrene 11,12-oxide, trans-11,12-dihydroxy-11,12-dihydro-3-methylcholanthrene, and 3-methylcholanthrene-1-one were inactive at the doses tested.

1,9,10-Trihydroxy-9,10-dihydro-3-methylcholanthrene at the 21- and 49-nmol doses also produced hepatic tumors in 50 and 81% of the male mice, respectively. 3-Methylcholanthrene and 2-hydroxy-3-methylcholanthrene had one-fourth to one-tenth the activity of 1,9,10-trihydroxy-9,10-dihydro-3-methylcholanthrene in the liver. The other 3-methylcholanthrene metabolites were essentially inactive in producing hepatic tumors. The high tumorigenic activity of 1,9,10-trihydroxy-9,10-dihydro-3-methylcholanthrene on mouse skin and in newborn mice provides evidence for bay-region activation of 3-methylcholanthrene to an ultimate carcinogen. The data also indicate that other metabolites of 3-methylcholanthrene may play a role in the carcinogenicity of this polycyclic aromatic hydrocarbon.