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

Heidi J. Einolf, Shantu Amin, Haruhiko Yagi, Donald M. Jerina, William M. Baird

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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-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 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-1,2,3,4-tetrahydro-B[c]Ph to deoxyadenosine [(-)-B[c]PhDE-2dA(t)] 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-1dA(c) and (+)-B[c]PhDE-1dA(t). 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-2dA(t), (+)-B[c]PhDE-1dA(t) and (+)-B[c]PhDE-1dA(c)] 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 capability of cells from humans to activate B[c]Ph to ultimate carcinogenic metabolites.

Original languageEnglish (US)
Pages (from-to)2237-2244
Number of pages8
JournalCarcinogenesis
Volume17
Issue number10
DOIs
StatePublished - Oct 1 1996

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Epoxy Compounds
Breast Neoplasms
Cell Line
Skin
DNA
DNA Adducts
benzo(c)phenanthrene
Epidermis
Inbred SENCAR Mouse
Deoxyguanosine

All Science Journal Classification (ASJC) codes

  • Cancer Research

Cite this

@article{6ac82cf210214296807b76aa54b660a0,
title = "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",
abstract = "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 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-1,2,3,4-tetrahydro-B[c]Ph to deoxyadenosine [(-)-B[c]PhDE-2dA(t)] 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-1dA(c) and (+)-B[c]PhDE-1dA(t). 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-2dA(t), (+)-B[c]PhDE-1dA(t) and (+)-B[c]PhDE-1dA(c)] 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 capability of cells from humans to activate B[c]Ph to ultimate carcinogenic metabolites.",
author = "Einolf, {Heidi J.} and Shantu Amin and Haruhiko Yagi and Jerina, {Donald M.} and Baird, {William M.}",
year = "1996",
month = "10",
day = "1",
doi = "10.1093/carcin/17.10.2237",
language = "English (US)",
volume = "17",
pages = "2237--2244",
journal = "Carcinogenesis",
issn = "0143-3334",
publisher = "Oxford University Press",
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}

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. / Einolf, Heidi J.; Amin, Shantu; Yagi, Haruhiko; Jerina, Donald M.; Baird, William M.

In: Carcinogenesis, Vol. 17, No. 10, 01.10.1996, p. 2237-2244.

Research output: Contribution to journalArticle

TY - JOUR

T1 - 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

AU - Einolf, Heidi J.

AU - Amin, Shantu

AU - Yagi, Haruhiko

AU - Jerina, Donald M.

AU - Baird, William M.

PY - 1996/10/1

Y1 - 1996/10/1

N2 - 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 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-1,2,3,4-tetrahydro-B[c]Ph to deoxyadenosine [(-)-B[c]PhDE-2dA(t)] 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-1dA(c) and (+)-B[c]PhDE-1dA(t). 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-2dA(t), (+)-B[c]PhDE-1dA(t) and (+)-B[c]PhDE-1dA(c)] 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 capability of cells from humans to activate B[c]Ph to ultimate carcinogenic metabolites.

AB - 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 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-1,2,3,4-tetrahydro-B[c]Ph to deoxyadenosine [(-)-B[c]PhDE-2dA(t)] 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-1dA(c) and (+)-B[c]PhDE-1dA(t). 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-2dA(t), (+)-B[c]PhDE-1dA(t) and (+)-B[c]PhDE-1dA(c)] 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 capability of cells from humans to activate B[c]Ph to ultimate carcinogenic metabolites.

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