Benzo(c)phenanthrene is activated to DNA-binding diol epoxides in the human mammary carcinoma cell line MCF-7 but only limited activation occurs in mouse skin

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Abstract
Benzo[c]phenanthrene (B[c]Ph) is an environmental contaminant with low carcinogenic activity in rodent bioassays. B[c]Ph-3, 4-diol-l, 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 μM B[c]Ph for 48, 72 and 96 h or to 1 μM (± )-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-l, 2, 3, 4-tetrahydro-B[c]Phtoeoxy-adenosine [(-)-B[c]PhDE-2dAt] and by the cis- and trans-addition of (4S, 3R)-dihydroxy-(2S, 1R)-epoxy-l, 2, 3, 4-tetra-hydro-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 μmol B[c]Ph for 24, 48 or 72 h or with 0.4 μmol (±)-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 μmol (±)-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 capabilityof cells from humans to activate B[c]Ph to ultimate carcinogenic metabolites.

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