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© 1993 Oxford University Press

research-article

Molecular analysis of DNA adducts and hprt mutations produced by 6-nitrosochrysene in Chinese hamster ovary cells

Mugimane G. Manjanatha, Ronald K. Newton 1, Roberta A. Mittelstaedt, Guglliemo R.D. Villani 2, K.Barry Declos 3 and Robert H. Heflich

National Center for Toxicological Research, Division of Genetic Toxicology Jefferson, AR 72079, USA
2Division of Biochemical Toxicology Jefferson, AR 72079, USA
3Universita degli Studi di Napoli, Dipartimento di Biochimica e Biotecnologie Mediche Napoli, Italy

We have characterized the mutational spectrum of 6-nitrosochrysene in the hprt gene of Chinese hamster ovary (CHO-K1) cells and also examined the adducts formed by this compound in CHO-K1 cells by quantitative 32P-postlabeling analysis. Seventy percent of the identified mutations were simple basepair substitutions, and they occurred more often at A:T (14/17) than at G:C. Furthermore, 13 of the basepair substitutions at A:T had the mutated dA, the probable adducted residue, on the non-transcribed DNA strand. The preference for mutation at A:T contrasted sharply with the distribution of adducts formed by 6-nitrosochrysene: 80% of the identified adducts were with dG, while only 20% were probably formed through binding with dA. Analyses conducted with excision-repair-defective CHO-UV5 cells revealed both a preference for basepair substitution at A:T and an adduct profile that were similar to those found for repair-proficient CHO-K1 cells. However, basepair substitutions from CHO-UV5 cell mutants had the mutated dAs distributed randomly between the non-transcribed and transcribed DNA stands. The mutational spectra found for solvent control CHO-K1 and CHO-UV5 cells differed from those of the 6-nitrosochrysene-treated cultures. These findings suggest that 6-nitrosochrysene-treated cultures. These findings suggest that 6-nitrosochrysene-induced mutations are targeted to DNA damage, but that 6-nitrosochrysene-derived dA adducts are much more effective at producing mutations than 6-nitrosochrysene-derived dG adducts. The extreme strand bias for mutated dAs in the CHO-K1 mutational spectrum appears to result from preferential removal of 6-nitrosochrysene-induced DNA lesions from the transcribed DNA strand.


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