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.
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.
Einolf
H J
HJ
Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN 47907, USA.
Amin
S
S
Yagi
H
H
Jerina
D M
DM
Baird
W M
WM
D000818:Animals; D001711:Biotransformation; D001943:Breast Neoplasms / Q000378:metabolism*; D015197:Carcinogenicity Tests / Q000379:methods*; D002277:Carcinoma / Q000378:metabolism*; D018736:DNA Adducts / Q000378:metabolism*; D004273:DNA, Neoplasm / Q000378:metabolism; D004852:Epoxy Compounds; D005260:Female; D006801:Humans; D051379:Mice; D010616:Phenanthrenes / Q000378:metabolism*; D012867:Skin / Q000378:metabolism*; D013045:Species Specificity; D014407:Tumor Cells, Cultured
D018736:DNA Adducts; D004273:DNA, Neoplasm; D004852:Epoxy Compounds; D010616:Phenanthrenes; C002615:benzo(c)phenanthrene