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Rates of Hydrolysis and Extents of DNA Binding of 5-Methylchrysene Dihydrodiol Epoxides¹

Naylor Dana Institute for Disease Prevention, American Health Foundation, Valhalla, New York 10595 [A. A. M., J. M. L., S. A., S. S. H., D. H.], and the Ben May Laboratory for Cancer Research, University of Chicago, Chicago, Illinois 60637 [J. P., R. G. H.]

The rates of hydrolysis in the absence and presence of native and denatured DNA, and the extents of DNA binding of five dihydrodiol epoxides derived from 5-methylchrysene (5-MeC) and chrysene have been determined. The compounds studied were: trans-1,2-dihydroxy-anti-3,4-epoxy-1,2,3,4-tetrahydro-5-MeC; trans-7,8-dihydroxy-anti-9,10-epoxy-7,8,9,10-tetrahydro-5-Mec; trans-1,2-dihydroxy-syn-3,4-epoxy-1,2,3,4-tetrahydro-5-MeC; trans-7,8-dihydroxy-syn-7,8,9,10-tetrahydro-5-MeC; and trans-1,2-dihydroxy-anti-3,4-epoxy-1,2,3,4-tetrahydrochrysene. In the absence of DNA, at pH 7 and 37°C half-lives of trans-1,2-dihydroxy-syn-3,4-epoxy-1,2,3,4-tetrahydro-5-MeC and trans-1,2-dihydroxy-anti-3,4-epoxy-1,2,3,4-tetrahydro-5-MeC were similar, t = 62 and 59 min, while trans-7,8-dihydroxy-syn-9,10-epoxy-7,8,9,10-tetrahydro-5-MeC hydrolyzed faster than trans-7,8-dihydroxy-anti-9,10-epoxy-7,8,9,10-tetrahydro-5-MeC, t = 5.4 versus 17.5 min; trans-1,2-dihydroxy-anti-3,4-epoxy-1,2,3,4-tetrahydrochrysene had the slowest rate of hydrolysis, t = 104 min. Studies of the effects of native and denatured DNA on the rates of hydrolysis of the dihydrodiol epoxides indicated that native DNA remarkably accelerated these rates for all dihydrodiol expoxides, but the degree of acceleration varied for the different dihydrodiol epoxides. The acceleration of hydrolytic rates by native DNA relative to that by denatured DNA was correlated with the covalent binding of these dihydrodiol epoxides with DNA in vitro. The catalytic effect of DNA in enhancing the rates of hydrolysis of dihydrodiol epoxides and the relative extents of covalent binding of the dihydrodiol epoxides to DNA were in the following order: trans-1,2-dihydroxy-anti-3,4-epoxy-1,2,3,4-tetrahydro-5-MeC > trans-7,8-dihydroxy-anti-9,10-epoxy-7,8,9,10-tetrahydro-5-MeC > trans-1,2-dihydroxy-anti-3,4-epoxy-1,2,3,4-tetrahydrochrysene > trans-1,2-dihydroxy-syn-3,4-epoxy-1,2,3,4-tetrahydro-5-MeC > trans-7,8-dihydroxy-syn-9,10-epoxy-7,8,9,10-tetrahydro-5-MeC. The results of this study suggest that physical interactions with DNA are important in determining the relative extents of binding of these dihydrodiol epoxides to DNA in vitro.

¹ This study was supported by Grants CA32242 and CA36097 from the National Cancer Institute. This is paper 78 of the series, "A Study of Chemical Carcinogenesis."

² To whom requests for reprints should be addressed.

Received 9/28/84. Revised 2/ 4/85. Accepted 2/ 6/85.

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