BENZO[C]PHENANTHRENE IS ACTIVATED TO DNA-BINDING DIOL EPOXIDES IN THEHUMAN MAMMARY-CARCINOMA CELL-LINE MCF-7 BUT ONLY LIMITED ACTIVATION OCCURS IN MOUSE SKIN

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-epoxid es (B[c]PhDE), however, are among the most tumorigenic diol epoxides k nown, To determine whether human cells are capable of activating B[c]P h to DNA-binding metabolites, cultures of the human mammary cell line, MCF-7, were exposed to 10 mu M B[c]Ph for 48, 72 and 96 h or to 1 mu M [(+/-)-B[c]Ph-3,4-dihydrodiol for 48 h. The B[c]Ph-DNA adducts were analyzed by P-33-postlabeling and reverse-phase HPLC. The major B[c]Ph -DNA adducts were formed by the trans-addition -dihydroxy-(2S,1R)-epox y-1,2,3,4-tetrahydro-B[c]Ph to deoxyadenosine [(-)-B[c]PhDE-2dA(t)] an d by the cis- and trans-addition of -dihydroxy-(2S,1R)-epoxy-1,2,3,4-t etrahydro-B[c]Ph to deoxyadenosine [(-)-B[c]PhDE-2dA(c)] and (+)-B[c]P hDE-1d(t)]. Smaller amounts of the trans-addition of (-)-B[c]PhDE-2 we re bound to deoxyguanosine. To determine whether B[c]Ph can be metabol ically activated to diol epoxides in mouse epidermis, female SENCAR mi ce were treated topically with 2 mu mol B[c]Ph for 24, 48 or 72 h or w ith 0.4 mu mol (+/-)-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 de tected B[c]PhDE-2dA(t), (+)-B[c]PhDE-1dA(t) and (+)-B[c]PhDE-1dA(c)] a t 24, 48 and 72 h. In contrast, mice treated topically with 0.4 mu mol (+/-)-B[c]Ph-3,4-dihydrodiol formed B[c]PhDE-DNA adducts at levels 6-f old greater than those observed with B[c]Ph at 48 h. The higher format ion 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 tumorigeni city 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 ad equately assess the potential capability cells from humans to activate B[c]Ph to ultimate carcinogenic metabolites.