Comparison of the binding of some carcinogenic and non-carcinogenic cyclopenta[a]phenanthrenes to DNA in vitro and in vivo.
After microsomal activation in vitro, both the strong carcinogen 15,16-dihydro-11-methylcyclopenta[a]phenanthren-17-one and its inactive 12-methyl isomer bind covalently to added DNA, in the ratio approximately 6:1 (1595 and 254 mu mol/mol of DNA phosphorus, respectively). Over a thousand times less binding was observed when DNA was isolated from the skin of groups of mice that had received a topical dose of 1000 nmol of these two compounds, and of the unsubstituted ketone (non-carcinogen) and its 11,12-dimethyl derivative (carcinogen), 48 h previously; the binding ratios were 458, 155, 19 and 974 nmol/mol DNA phosphorus, respectively. Covalent binding of the 11-methyl compound to mouse skin DNA, measured 48 h after topical application, was linear with dose over the range 50 - 1000 nmol. It has previously been demonstrated for groups of mice initiated with 200 or 400 nmol of this carcinogen and promoted by repeated application of croton oil that skin tumour incidences were 50 and 70%, respectively. For a topical dose of 1000 nmol of the inactive 12-methyl isomer DNA binding in skin falls in this range, equivalent to DNA binding given by approximately 340 nmol of the carcinogen. Thus although the inactive unsubstituted parent compound essentially fails to bind to skin DNA after topical application, there does not seem to be a consistent relationship between extent of DNA binding in vivo and carcinogenicity among these cyclopenta[a]phenanthrenes. However, loss of the 12-methyl adducts from skin followed a logarithmic course over the first 10 days following application, with a half life of 3.5 days. In contrast, it was previously shown that removal of the 11-methyl adducts could not be measured above the normal rate of DNA turnover for this mouse tissue (half life, 6-7 days). It is suggested that active DNA repair of the 12-methyl lesions may contribute to the lack of activity of this isomer.
D000818:Animals; D002273:Carcinogens / Q000378:metabolism*; D004247:DNA / Q000378:metabolism*; D006067:Gonanes / Q000378:metabolism*; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D012867:Skin / Q000378:metabolism*
D002273:Carcinogens; D006067:Gonanes; D004247:DNA