Benzo[c]phenanthrene (B[c]Ph) is an environmental contaminant with low carcinogenic activity in rodent bioassays. B[c]Ph-3,4-diol-1,2-
epoxides (
B[c]PhDE), however, are among the most tumorigenic diol
epoxides known. To determine whether human cells are capable of activating B[c]Ph to
DNA-binding metabolites, cultures of the human mammary cell line, MCF-7, were exposed to 10 microM B[c]Ph for 48, 72 and 96 h or to 1 microM (+/-)-B[c]Ph-3,4-
dihydrodiol for 48 h. The B[c]Ph-
DNA adducts were analyzed by 33P-postlabeling and reverse-phase HPLC. The major B[c]Ph-
DNA adducts were formed by the trans-addition of (4R,3S)-dihydroxy-(2S,1R)-epoxy-1,2,3,4-tetrahydro-B[c]Ph to
deoxyadenosine [(-)-
B[c]PhDE-2dAt] and by the cis- and trans-addition of (4S,3R)-dihydroxy-(2S,1R)-epoxy-1,2,3,4-tetrahydro-B[c]Ph to
deoxyadenosine [(+)-
B[c]PhDE-1dAc and (+)-
B[c]PhDE-1dAt]. Smaller amounts of the trans-addition of (-)-
B[c]PhDE-2 were bound to
deoxyguanosine. To determine whether B[c]Ph can be metabolically activated to diol
epoxides in mouse epidermis, female SENCAR mice were treated topically with 2 micromol B[c]Ph for 24, 48 or 72 h or with 0.4 micromol (+/-)-B[c]Ph-3,4-
dihydrodiol for 24 or 48 h. In B[c]Ph-treated mice, only small amounts of three
B[c]PhDE-
DNA adducts were detected [(-)-
B[c]PhDE-2dAt, (+)-
B[c]PhDE-1dAt and (+)-
B[c]PhDE-1dAc] at 24, 48 and 72 h. In contrast, mice treated topically with 0.4 micromol (+/-)-B[c]Ph-3,4-
dihydrodiol formed
B[c]PhDE-
DNA adducts at levels 6-fold greater than those observed with B[c]Ph at 48 h. The higher formation of
B[c]PhDE-
DNA adducts by (+/-)-B[c]Ph-3,4-
dihydrodiol correlates with the greater potency of (+/-)-B[c]Ph-3,4-
dihydrodiol than of B[c]Ph as a
tumor initiator in mouse skin. The low extent of formation of
B[c]PhDE from B[c]Ph in mouse epidermis may explain the low tumorigenicity of B[c]Ph in this tissue. These results indicate activation of B[c]Ph in mouse skin and
tumorigenesis results in that tissue may not adequately assess the potential capability of cells from humans to activate B[c]Ph to ultimate carcinogenic metabolites.