Selective effects of selenium selenite on 7,12-dimethylbenz(a)anthracene-DNA binding in fetal mouse cell cultures.

Sodium selenite inhibits the binding of 7,12-dimethylbenz(a)anthracene (DMBA) to DNA in tertiary cultures of fetal mouse cells in a rather selective fashion. Inhibition can be demonstrated at 6 but not at 3 h after DMBA addition to the cells. Inhibition is seen after treatment of the cells with DMBA concentrations of 0.05 or 0.1 micrograms/ml but not after treatment at 0.01 micrograms/ml. Furthermore the inhibition seen with up to 1 microgram selenium/ml is selective in that products from the anti bay region dihydrodiol epoxide metabolite (where the epoxide oxygen is trans to the 4-hydroxy group) are suppressed while those from the syn-dihydrodiol-epoxide (where the epoxide oxygen is cis to the 4-hydroxy group) are not affected. In the absence of selenite, it was found that syn-dihydrodiol epoxide-DNA adducts are formed in a roughly linear fashion with time over a range of DMBA concentration. In contrast, the capacity of the cells to generate anti-dihydrodiol-epoxide adducts in a 3-h interval is saturated at concentrations of DMBA above 0.025 micrograms/ml and after the initial 3-h period the cells generate these adducts at up to a 6-fold greater rate than during the initial 3 h. This increase in rate of formation of anti-dihydrodiol-epoxide products is inhibited by actinomycin D and appears to be a consequence of DMBA inducing an enzyme activity which selectively generates the anti-dihydrodiol-epoxide and not the syn-dihydrodiol-epoxide. The selective action of sodium selenite in inhibiting only anti-dihydrodiol-epoxide product formation and doing this only at certain times and at certain doses of DMBA is a result of the fact that it inhibits the induction process. Once induction has occurred, sodium selenite is no longer inhibitory of DMBA-DNA binding. The chemopreventive action of selenium in chemical carcinogenesis could be partially attributable to effects such as those described herein on carcinogen-DNA binding. It is also possible, however, that the chemopreventive actions of selenium might be attributable to effects on the expression of genes other than those involved in carcinogen metabolism.