Low absolute mutagenic efficiency but high cytotoxicity of a non-bay region diol epoxide derived from benzo[a]pyrene.
Insights into the mechanisms of chemical carcinogenesis can sometimes be gained by comparing the effects of closely related chemicals which differ in carcinogenic potency. We have treated Chinese hamster ovary (CHO) cells with a non-carcinogenic metabolite of benzo[a]pyrene, 9r,10t-dihydroxy-7c,8c-oxy-7,8,9,10-tetrahydrobenzo[a]pyrene (BPDE-III), and measured the formation and persistence of DNA adducts. We have correlated this binding data with cytotoxicity and mutagenicity in a DNA-repair-proficient CHO cell line (AT3-2) and in two derived lines, UVL-1 and UVL-10, which are unable to repair bulky DNA adducts. These data are compared with similar studies of the effects of the carcinogenic metabolite, 7r,8t-dihydroxy-9t,10t-oxy-7,8,9,10-tetrahydrobenzo[a]pyrene (BPDE-I). Synchronous fluorescence spectroscopy was used to measure the levels of BPDE-III-DNA adducts in treated cells. Adduct levels increased linearly with dose, but the absolute binding levels were about 30-fold lower than in comparable incubations with BPDE-I. Measurements of the removal of adducts derived from these two diol epoxides indicated no significant difference in the rate of repair measured 24 h post-treatment. When cells were treated with increasing doses of BPDE-III, survival curves were obtained which exhibited a shoulder region at low doses and an exponential decrease in plating efficiency at higher doses. By comparison of the D0's, the DNA-repair-deficient cell lines were found to be 4-5-fold more sensitive to the killing effects of BPDE-III than were the repair-proficient AT3-2 cells.
MacLeod
M C
MC
Science Park-Research Division, University of Texas M.D. Anderson Cancer Center, Smithville 78957.
Adair
G
G
Daylong
A
A
Lew
L
L
Humphrey
R M
RM
D015123:7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide / Q000378:metabolism*; D000228:Adenine Phosphoribosyltransferase / Q000235:genetics; D000818:Animals; D001580:Benzopyrenes / Q000633:toxicity*; D016466:CHO Cells; D015197:Carcinogenicity Tests; D002470:Cell Survival / Q000187:drug effects; D006224:Cricetinae; D004247:DNA / Q000378:metabolism*; D018736:DNA Adducts; D004260:DNA Repair / Q000187:drug effects*; D004852:Epoxy Compounds / Q000633:toxicity*; D005453:Fluorescence; D007041:Hypoxanthine Phosphoribosyltransferase / Q000235:genetics; D007700:Kinetics; D016296:Mutagenesis / Q000235:genetics*; D009152:Mutagenicity Tests; D009154:Mutation / Q000235:genetics
C057268:7,8-dihydroxy-9,10-oxy-7,8,9,10-tetrahydrobenzo(a)pyrene-DNA adduct; D001580:Benzopyrenes; D018736:DNA Adducts; D004852:Epoxy Compounds; D015123:7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide; C072019:benzo(a)pyrene diolepoxide I; C072116:BPDE-II; C072117:BPDE-III; D004247:DNA; D000228:Adenine Phosphoribosyltransferase; D007041:Hypoxanthine Phosphoribosyltransferase