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Influence of the Alkyl Substituent on Mutagenicity and Covalent DNA Binding of Bay Region Diol-Epoxides of 7-Methyl- and 7-Ethylbenz(a)anthracene in Salmonella and V79 Chinese Hamster Cells¹

Department of Toxicology of the University, Obere Zahlbacher Strasse 67, D-6500 Mainz, Federal Republic of Germany [H. G.]; Ben May Institute, University of Chicago, Chicago, Illinois 60637 [R. G. H.]; and Chester Beatty Laboratories, Institute of Cancer Research, Fulham Road, London, SW3 6JB, England [D. H. P., A. H., P. L. G.]

The anti-isomers of the bay region diol-epoxides of the strong carcinogen 7-methylbenz(a)anthracene and of the weak carcinogen 7-ethylbenz(a)anthracene were investigated for mutagenicity in Salmonella typhimurium (reversion of the his^- strains TA98 and TA100 to prototrophy) and V79 Chinese hamster cells (acquisition of resistance to 6-thioguanine and ouabain; formation of micronuclei). In addition, in the V79 cells, the levels of the DNA adducts formed were determined by ³²P-postlabeling analysis. In terms of mutations per nmol compound administered, the methyl derivative was four to 10 times more potent, depending on the genetic endpoint, than its ethyl congener. However, when the results were expressed as mutations per adduct, the difference between the two diol-epoxides was small. Therefore, a higher level of DNA modification appears to be the major reason for the stronger mutagenicity of the methyl derivative. However, both diol-epoxides had similar half-lives (about 9 min) in physiological buffer, as determined from the decline in mutagenic activity after preincubation of the test compound. These results suggest that the effect of the 7-alkyl group on the extent of reaction with DNA is more a result of steric factors than of a change in the intrinsic chemical reactivity of the diol-epoxides.

¹ This work was supported by the Deutsche Forschungsgemeinschaft (SFB-302), by a grant (CA-36097) from the National Cancer Institute to R. G. H., and by grants to the Institute of Cancer Research by the Medical Research Council and the Cancer Research Campaign.

² To whom requests for reprints should be addressed.

Received 9/19/88. Revised 12/28/88. Accepted 1/ 5/89.