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Interaction between Normal Human Diploid Cells and Chemical Carcinogens/Mutagens In Vitro.

Huang-SL; Waters-MD
NIOSH 1988:435-464
Cultured human cells were used to clarify the effects of DNA alterations at the hypoxanthine-phosphoribosyl-transferase (HPRT) locus generated by a chemical mutagen, benzo(a)pyrene (50328) (BaP), or ionizing radiation (gamma rays) on mutation frequency. DNA/BaP adduct formation was quantitatively compared to mutation frequency in treated human cells by means of phosphorus-32 postlabeling techniques. Southern Blot analysis was used to evaluate the relationship between structural changes in the HPRT gene and modification of HPRT enzyme activity for spontaneous mutants and mutants recovered after gamma ray treatment. The study demonstrated a strong correlation between the frequency of mutations induced by BaP and the formation of DNA/BaP adducts, indicating that adduct formation was linked directly to the mutation process for this mutagen in this cell system. The effectiveness of metabolic activation by S-9 microsomes from rat livers was also demonstrated in this cell system. Mutant cell lines with DNA rearrangements or deletions generated by gamma irradiation demonstrated either none or greatly reduced HPRT enzyme activity, indicating such DNA alterations are directly responsible for the lost enzyme activity and are a component of the mutation process. Among spontaneous mutants and gamma ray induced mutants, the frequency of occurrence of various types of alterations was similar, indicating that size may contribute to the observed differences in response to radiation. The authors conclude that the environmental mutagenesis at the HPRT locus in cultured human cells was mediated by modifications of the genome, either by adduct formation as in the case of BaP or by base sequence changes as in the case of gamma radiation.
Cell-cultures; Carcinogens; Mutagens; Enzyme-activity; Nucleic-acids; Mutagenicity; Radiation-exposure; Humans; In-vitro-studies; DNA-adducts;
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Proceedings of the Fourth NCI/EPA/NIOSH Collaborative Workshop: Progress on Joint Environmental and Occupational Cancer Studies, April 22-23, 1986, Rockville, Maryland, NIH Publication No. 88-2960