Benzo[j]fluoranthene (B[j]F), trans-4,5-dihydro-4,5-dihydroxy-B[j]F, and trans-9,10-dihydro-9,10-dihydroxy-B[j]F were evaluated for tumorigenic activity in newborn CD1 mice. These dihydrodiols were assayed at doses of 1.10 and 0.275 µmol/mouse. B[j]F and the syn- and anti-diol epoxides derived from these dihydrodiols were evaluated at doses of 1.10, 0.275, and 0.110 µmol/mouse (80 mice/group). trans-4,5-Dihydro-4,5-dihy-droxy-B[j]F was more potent than trans-9,10-dihydro-9,10-dihydroxy-B[j]F in inducing pulmonary tumors in both female and male mice. Administration of 1.10 µmol of trans-4,5-dihydro-4,5-dihydroxy-B[j]F resulted in a 90-92% incidence of pulmonary tumors with an average of 3.6 and 4.2 tumors/mouse among female and male mice, respectively. A similar tumorigenic activity was observed for B[j]F in lung. trans-9,10-Dihydro-9,10-dihydroxy-B[j]F was significantly less tumorigenic (P < 0.05), producing a 44 and 64% incidence of pulmonary tumors at a dose of 1.10 µmol with an average of 0.8 and 1.0 tumor/mouse in female and male mice, respectively. A statistically significant (P < 0.001) incidence of hepatic tumors was also produced among male mice administered either B[j]F, trans-4,5-dihydro-4,5-dihydroxy-B[j]F, or trans-9,10-dihydro-9,10-dihydroxy-B[j]F at a dose of 1.10 µmol/mouse. In comparing the tumorigenicity of the diasteromeric diol epoxides derived from both trans-4,5-dihydro-4,5-dihydroxy-B[j]F and trans-9,10-dihydro-9,10-dihydroxy-B[j]F, the anti-diasteromers exhibited greater tumorigenic activity. The most tumorigenic diol epoxide was anti-4,5-dihydroxy-6,6a-epoxy-4,5,6,6a-tetrahydro-B[j]F. At a dose of 0.275 µmol, this diol epoxide induced a 96 and 100% incidence of pulmonary tumors in female and male mice, with an average of 8.6 and 5.0 tumors/mouse, respectively. anti-9,10-Dihydroxy-11,12-epoxy-9,10,11,12-tetrahydro-B[j]F at this dose produced a 56 and 95% incidence of pulmonary tumors in female and male mice with an average of 1.0 and 2.8 tumors/mouse, respectively. syn-4,5-Dihydroxy-6,6a-epoxy-4,5,6,6a-tetrahydro-B[j]F and syn-9,10-dihydroxy-11,12-epoxy-9,10,11,12-tetrahydro-B[j]F at a dose of 0.275 µmol did not induce a significant incidence (P > 0.05) of pulmonary tumors in female or male mice. These data suggest that anti-4,5-dihydroxy-6,6a-epoxy-4,5,6,6a-tetrahydro-B[j]F may be the principal ultimate carcinogenic form of B[j]F responsible for the induction of lung tumors in newborn mice. In contrast to their anti-isomers, syn-4,5-dihydroxy-6,6a-epoxy-4,5,6,6a-tetrahydro-B[j]F and syn-9,10-dihydroxy-11,12-epoxy-9,10,11,12-tetrahydro-B[j]F did not induce a significant incidence of liver tumors in male mice at a total dose of 0.110 µmol. anti-4,5-Dihydroxy-6,6a-epoxy-4,5,6,6a-tetrahydro-B[j]F and awri-9,10-dihydroxy-11,12-epoxy-9,10,11,12-tetrahydro-B[j]F at total doses of 0.110 and 0.275 µmol had comparable tumorigenic activity in the liver of male newborn mice. These results suggest that either one or both of the activation pathways associated with the formation of these electrophilic metabolites could contribute to the hepatocarcinogenic activity observed for B[j]F in newborn male mice.
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This publication was made possible by Grant ES-02030 from the National Institute for Environmental Health Sciences, NIH. Presented in part at the annual meeting of the American Association for Cancer Research, San Diego, CA, May 1992.