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Tumorigenicity of the Dihydrodiols of Dibenzo(a,h)anthracene on Mouse Skin and in Newborn Mice

Department of Biochemistry and Drug Metabolism, Hoffmann-La Roche Inc., Nutley, New Jersey 07110 [M. K. B., W. L., A. W. W., R. L. C., A. H. C.], and Section on Oxidation Mechanisms, Laboratory of Bioorganic Chemistry, National Institute of Arthritis, Metabolism, and Digestive Diseases, NIH, Bethesda, Maryland 20014 [H. Y., J. M. K., D. M. J.]

Dibenzo(a,h)anthracene and the three metabolically possible trans-dihydrodiols of dibenzo(a,h)anthracene were tested for tumorigenic activity on mouse skin and in newborn mice. In the tumorigenicity study on mouse skin, a single topical application of 10 to 160 nmol of compound was followed 7 days later by twice-weekly applications of the tumor promoter 12-O-tetradecanoylphorbol-13-acetate for 25 weeks. Comparisons of the percentage of mice with tumors and number of tumors per mouse indicated that dibenzo(a,h)anthracene and dibenzo(a,h)anthracene 3,4-dihydrodiol were approximately equipotent as tumor initiators. The 1,2- and 5,6-dihydrodiols of dibenzo(a,h)anthracene had no significant tumor-initiating activity at the doses tested. Saturation of the double bond at position 1,2 of dibenzo(a,h)anthracene 3,4-dihydrodiol resulted in the formation of a tetrahydrodiol with markedly less tumor-initiating activity than dibenzo(a,h)anthracene 3,4-dihydrodiol. 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 70 or 420 nmol. The experiment was terminated when the animals were 25 to 29 weeks old. Less than 20% of control mice or mice treated with the 1,2 or 5,6-dihydrodiol of dibenzo(a,h)anthracene developed pulmonary tumors, and the average number of tumors per mouse was less than 0.25. In mice treated with 70 and 420 nmol of dibenzo(a,h)anthracene, 88 and 100%, respectively, developed pulmonary tumors with an average of 3.61 and 46.90 tumors/mouse. In mice treated with 70 and 420 nmol of dibenzo(a,h)anthracene 3,4-dihydrodiol, 83 and 99%, respectively, developed pulmonary tumors, with an average of 1.99 and 28.06 tumors/mouse. Hepatic neoplastic nodules were found in 42% of the male mice treated with 420 nmol of the 3,4-dihydrodiol of dibenzo(a,h)anthracene, but not in female mice or in mice from any of the other treatment groups. The high tumorigenic activity of dibenzo(a,h)anthracene 3,4-dihydrodiol on mouse skin and in the lung and liver of newborn mice, together with the lower tumorigenic activity of 3,4-dihydroxy-1,2,3,4-tetrahydrodibenzo(a,h)anthracene on mouse skin, provides support for bay-region activation of dibenzo(a,h)anthracene to an ultimate carcinogen.

¹ To whom requests for reprints should be addressed.

² Recipient of National Cancer Institute Grant 1 F32 CA05729-01.

Received 11/ 9/78. Accepted 1/ 2/79.