Tumorigenicity of the Diastereomeric Benz[a]anthracene 3,4-Diol-1,2-epoxides and the (+)- and (−)-Enantiomers of Benz[a]anthracene 3,4-Dihydrodiol in Newborn Mice

• Published in: JNCI : Journal of the National Cancer Institute 1979-07, Vol.63 (1), p.201-204
• Main Authors: Wislocki, Peter G., Buening, Mildred K., Levin, Wayne, Lehr, Roland E., Thakker, Dhiren R., Jerina, Donald M., Conney, Allan H.
• Format: Article
• Language: English
• Subjects: Animals; Animals, Newborn; Benz(a)Anthracenes - metabolism; Benz(a)Anthracenes - toxicity; Carcinogens; Chemical Phenomena; Chemistry; Epoxy Compounds - toxicity; Female; Lung Neoplasms - chemically induced; Male; Mice
• ISSN: 0027-8874; 1460-2105; 1460-2105
• DOI: 10.1093/jnci/63.1.201

The tumorigenic activity of benz[a]anthracene (BA), the (+)- and (−)-enantiomers of trans-3,4-dihydroxy-3,4-dihydrobenz[a]anthracene (BA 3,4-dihydrodiol), and the racemic diastereomers of the BA 3,4-diol-1,2-epoxides [i.e., either or both of the diastereomeric 1,2-epoxides derived from BA 3,4-dihydrodiol in which the epoxide oxygen is cis (diol epoxide-1) or trans (diol epoxide-2) to the benzylic 4-hydroxyl group] was examined in newborn Swiss-Webster mice. The mice were administered ip a total dose of 280 nmoles of compound in divided doses consisting of 40 nmoles within 24 hours of birth, 80 nmoles at 8 days of age, and 160 nmoles at 15 days of age. The experiment was terminated when the animals were 26 weeks of age. BA 3,4-diol-1,2-epoxide-2 was the most potent compound tested. All animals treated with BA 3,4-diol-1,2-epoxide-2 developed pulmonary tumors with an average of 13.3 tumors per mouse. BA 3,4-diol-1,2-epoxide-1 produced pulmonary tumors in 42% of the mice with an average of only 0.56 tumors per mouse. The (−)-enantiomer of BA 3,4-dihydrodiol with [3R,4R] absolute stereochemistry was the second most tumortgenlc derivative of BA tested; it produced pulmonary tumors in 71% of the mice with an average of 1.88 tumors per mouse. BA and the (+)-enantiomer of BA 3,4-dihydrodiol had little or no tumorigenic activity at the dose tested. A comparison of the average number of pulmonary tumors per mouse revealed that BA 3,4-diol-1,2-epoxide-2 was about 30-fold more tumorigenic than was BA 3,4-diol-1,2-epoxide-1, 8-fold more tumorigenic than was (−)-BA 3,4-dihydrodiol, and greater than 85-fold more tumorigenic than was BA. These data indicate that in newborn mice BA 3,4-dihydrodiol and a BA 3,4-diol-1,2-epoxide are proximate and ultimate carcinogenic metabolites of BA, respectively.