Carcinogenesis, Vol. 20, No. 12, 2279-2286,
December 1999
© 1999 Oxford University Press
Carcinogenesis |
Characterization of the mutational profile of (+)-7R,8S-dihydroxy-9S,10R-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene at the hypoxanthine (guanine) phosphoribosyltransferase gene in repair-deficient Chinese hamster V-H1 cells
Laboratory for Cancer Research, Department of Chemical Biology, College of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ 08854,
1 Section on Oxidation Mechanisms, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA and
2 Department of Radiation Genetics and Chemical Mutagenesis, Leiden University–LUMC and J.A.Cohen Institute, Interuniversity Research Institute for Radiopathology and Radiation Protection, Leiden, The Netherlands
Earlier studies have shown that the profile of mutations induced by (+)-7R,8S-dihydroxy-9S,10R-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene [(+)-BPDE] at the hypoxanthine (guanine) phosphoribosyltransferase (hprt) gene of Chinese hamster V79 cells was dependent on the concentration of (+)-BPDE. In the present study, we examined the effect of the concentration of (+)-BPDE on its mutational profile at the hprt gene in repair-deficient V-H1 cells (a derivative of V79 cells) to explore the role of DNA repair in the dose-dependent mutational profile of (+)-BPDE. Independent hprt mutant clones were isolated after exposing V-H1 cells to dimethylsulfoxide (DMSO) or to low (4–6 nM; 95% cell survival) or high (40–48 nM; 31% cell survival) concentrations of (+)-BPDE in DMSO. The mutation frequencies for the DMSO control and for the low and high concentration groups were 0.1, 2.1 and 32.9 mutant colonies/105 survivors, respectively. The profile of mutations at the hprt gene was characterized for 148 (+)-BPDE-induced mutant clones and the results from the present study were compared with those obtained earlier with V79 cells. The data indicated that: (i) V-H1 cells were ~9-fold more sensitive to the cytotoxic effects of (+)-BPDE than V79 cells; (ii) the mutation frequency in V-H1 cells was similar to that observed in V79 cells following exposure to similar concentrations of (+)-BPDE; (iii) (+)-BPDE-induced mutations at guanine on the transcribed strand of the hprt gene were common in V-H1 cells but were extraordinarily rare in V79 cells; (iv) (+)-BPDE-induced mutations at adenine on the transcribed strand of the hprt gene were common in both V-H1 and V79 cells; (v) although exposure of V79 cells to different doses of (+)-BPDE resulted in a dose-dependent mutational profile at the hprt gene, this was not observed in V-H1 cells. Our observations indicate a defect in the transcription-coupled repair of (+)-BPDE–DNA adducts in V-H1 cells and that the repair activity deficient in V-H1 cells is essential for the dose-dependent mutational profile observed with (+)-BPDE in V79 cells.
Abbreviations: (+)-BPDE, (+)-7R,8S-dihydroxy-9S,10R-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene; (–)-B[c]PhDE, (–)-(1R,2S,3S,4R)-3,4-dihydroxy-1,2-epoxy-1,2,3,4-tetrahydrobenzo[c]phenanthrene; DMSO, dimethyl sulfoxide; hprt, hypoxanthine (guanine) phosphoribosyltransferase.
3 To whom correspondence should be addressedEmail: swei{at}rci.rutgers.edu
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