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Evidence for the Involvement of a Bis-Diol-Epoxide in the Metabolic Activation of Dibenz[a,h]anthracene to DNA-binding Species in Mouse Skin¹

Institute of Cancer Resarch, Haddow Laboratories, Cotswold Road, Belmont, Sutton, Surrey, SM2 5NG, United Kingdom [P. L. C., M. N. S., S. L., D. H. P., P. L. G.], and Institute of Toxicology, University of Mainz, Obere Zahlbacher Str. 67, D-6500 Mainz, Germany [K. L. P., F. O.]

Dibenz[a,h]anthracene (DB[a,h]A) and its microsomal metabolites, trans-3,4-dihydro-3,4-dihydroxydibenz[a,h]anthracene (DBA-3,4-diol), trans, trans-3,4:8,9-tetrahydro-3,4:8,9-tetrahydroxydibenz[a,h]anthracene trans,trans-3,4:10,11-tetrahydro-3,4:10,11-tetrahydroxydibenz[a,h]anthracene (DBA-3,4,10,11-bis-diol) and trans,trans-3,4:12,13-tetrahydro-3,4:12,13-tetrahydroxydibenz[a,h]anthracene were each applied topically to mouse skin and the epidermal DNA isolated 24 h later. ³²P-postlabeling analysis of each of the DNA samples was performed. DNA from mice treated with DB[a,h]A produced an adduct map on TLC consisting of one major and three minor adduct spots. A similar pattern of spots was produced by DBA-3,4-diol. No detectable DNA adducts were produced by trans,trans-3,4:12,13-tetrahydro-3,4:12,13-tetrahydroxydibenz[a,h]anthracene, although a single, minor adduct spot was produced by trans,trans-3,4:8,9-tetrahydro-3,4:8,9-tetrahydroxydibenz[a,h]-anthracene. However, DBA-3,4,10,11-bis-diol was found to produce a major single adduct that comigrated on thin layer chromatography with the major adduct produced by both DB[a,h]A and DBA-3,4-diol. In addition, this adduct was present at a level 10 times higher than the corresponding adduct produced by treatment with the parent hydrocarbon. Coelution of the major adducts formed from DB[a,h]A and DBA-3,4-diol with that formed from DBA-3,4,10,11-bis-diol was also demonstrated on reverse-phase high performance liquid chromatography. Thus, we propose that, in mouse skin, the major pathway of DB[a,h]A activation to DNA binding products is via a 3,4-diol to the 3,4,10,11-bis-diol and ultimately to a bis-diol-epoxide (potentially the 3,4,10,11-bis-dihydrodiol-1,2-oxide).

¹ This work was supported, in part, by USPHS Grant CA21959, awarded by the National Cancer Institute, Department of Health and Human Services, and, in part, by grants to the Institute of Cancer Research from the Medical Research Council and the Cancer Research Campaign.

² To whom requests for reprints should be addressed.

Received 11/17/92. Accepted 1/15/93.

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