Journal article
Role of Cytochrome P450 Enzyme Induction in the Metabolic Activation of Benzo[c]phenanthrene in Human Cell Lines and Mouse Epidermis
Chemical research in toxicology, Vol.10(5), pp.609-617
05/01/1997
DOI: 10.1021/tx960174n
PMID: 9168260
Abstract
The environmental contaminant benzo[c]phenanthrene (B[c]Ph) has weak carcinogenic activity in rodent bioassays; however, the fjord region diol epoxides of B[c]Ph, B[c]Ph-3,4-diol 1,2-epoxides (B[c]PhDE), are potent carcinogens. To determine the role of cytochrome P450 isozymes in the activation of B[c]Ph in MCF-7 cells and the low activation of B[c]Ph in mouse skin, cells of the MCF-7 and the human hepatoma HepG2 cell lines were treated with the potent Ah receptor agonist 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) prior to exposure to B[c]Ph for 24 h. Mice were treated topically with 1/μg of TCDD or vehicle (control) for 73 h and then with 2/μmol of B[c]Ph for 24 h. In MCF-7 cells, TCDD exposure increased B[c]PhDE-DNA adduct levels more than 3-fold with a 10-fold increase in the (-)-B[c]PhDE-2-dA(t) adduct. Treatment of HepG2 cells with TCDD prior to B[c]Ph application did not increase B[c]PhDE-DNA binding. Total B[c]PhDE-DNA adducts increased 3-fold in TCDD-treated mouse epidermis: the majority of the increase resulted from (+)- B[c]PhDE-1-dA adducts. Analysis of P450 enzymes by Western blotting detected a large increase of P4501B1 but almost no increase in P4501A1 in MCF-7 cells exposed to 10 μM B[c]Ph for 24 or 48 h. In HepG2 cells, there were no detectable levels of P4501A1 or P4501B1 after treatment with 10 μM B[c]Ph for 24 h. In contrast, topical application of 2 μmol of B[c]Ph to mouse skin for 48 or 72 h increased P4501A1, but no P4501B1 was detected. As a measure of P450 activity, the metabolism of 7,12-dimethylbenz[a]anthracene (DMBA) was analyzed in microsomes prepared from MCF-7 and HepG2 cells exposed to 0.1% DMSO, 10 μM B[c]Ph, or 10 nM TCDD for 24 or 48 h and from mouse epidermis treated with 1 μg of TCDD, or vehicle control for 72 h, or 2μmol of B[c]Ph for 48 h. The levels of DMBA metabolites were low or undetectable in microsomes from B[c]Ph-treated MCF-7 and HepG2 cells, but a metabolite pattern consistent with P4501A1 metabolism of DMBA was present in B[c]Ph- exposed mouse epidermal microsomes. TCDD-treated MCF-7 cells, HepG2 cells, and mouse epidermis had DMBA metabolism patterns characteristic of P4501A1 activity. Microsomes from TCDD-treated human cells formed a higher proportion of the proximate carcinogenic metabolite DMBA-3,4-dihydrodiol (16% of total identified metabolites) than TCDD-treated mouse epidermis (2%). In mouse epidermis, the weak ability of B[c]Ph to increase hydrocarbon-metabolizing activity and the increase in mainly P4501A1, leading to formation of the less carcinogenic stereoisomer B[c]PhDE-1, may explain the low carcinogenic activity of B[c]Ph. In a human mammary carcinoma cell line, treatment with B[c]Ph increases mainly P4501B1 and results in formation of a higher proportion of the more carcinogenic B[c]PhDE-2. This indicates that cells in which B[c]Ph treatment increases P4501B1 levels effectively activate B[c]Ph to potent carcinogenic metabolites.
Details
- Title: Subtitle
- Role of Cytochrome P450 Enzyme Induction in the Metabolic Activation of Benzo[c]phenanthrene in Human Cell Lines and Mouse Epidermis
- Creators
- Heidi J Einolf - Department of Medicinal Chemistry & Molecular Pharmacology, Purdue University, West Lafayette, Indiana 47907, Department of Pharmacology & Toxicology, University of New Mexico, Albuquerque, New Mexico 87131-1066, Department of Pharmacology, University of Wisconsin, Madison, Wisconsin 53706, Department of Pharmacology and Molecular Toxicology, University of Massachusetts Medical Center, Worcester, Massachusetts 01655-0126, NIDDK, The National Institutes of Health, Bethesda, Maryland 20892, Naylor DanaWilliam T Story - Department of Medicinal Chemistry & Molecular Pharmacology, Purdue University, West Lafayette, Indiana 47907, Department of Pharmacology & Toxicology, University of New Mexico, Albuquerque, New Mexico 87131-1066, Department of Pharmacology, University of Wisconsin, Madison, Wisconsin 53706, Department of Pharmacology and Molecular Toxicology, University of Massachusetts Medical Center, Worcester, Massachusetts 01655-0126, NIDDK, The National Institutes of Health, Bethesda, Maryland 20892, Naylor DanaCraig B Marcus - Department of Medicinal Chemistry & Molecular Pharmacology, Purdue University, West Lafayette, Indiana 47907, Department of Pharmacology & Toxicology, University of New Mexico, Albuquerque, New Mexico 87131-1066, Department of Pharmacology, University of Wisconsin, Madison, Wisconsin 53706, Department of Pharmacology and Molecular Toxicology, University of Massachusetts Medical Center, Worcester, Massachusetts 01655-0126, NIDDK, The National Institutes of Health, Bethesda, Maryland 20892, Naylor DanaMichele C Larsen - Department of Medicinal Chemistry & Molecular Pharmacology, Purdue University, West Lafayette, Indiana 47907, Department of Pharmacology & Toxicology, University of New Mexico, Albuquerque, New Mexico 87131-1066, Department of Pharmacology, University of Wisconsin, Madison, Wisconsin 53706, Department of Pharmacology and Molecular Toxicology, University of Massachusetts Medical Center, Worcester, Massachusetts 01655-0126, NIDDK, The National Institutes of Health, Bethesda, Maryland 20892, Naylor DanaColin R Jefcoate - Department of Medicinal Chemistry & Molecular Pharmacology, Purdue University, West Lafayette, Indiana 47907, Department of Pharmacology & Toxicology, University of New Mexico, Albuquerque, New Mexico 87131-1066, Department of Pharmacology, University of Wisconsin, Madison, Wisconsin 53706, Department of Pharmacology and Molecular Toxicology, University of Massachusetts Medical Center, Worcester, Massachusetts 01655-0126, NIDDK, The National Institutes of Health, Bethesda, Maryland 20892, Naylor DanaWilliam F Greenlee - Department of Medicinal Chemistry & Molecular Pharmacology, Purdue University, West Lafayette, Indiana 47907, Department of Pharmacology & Toxicology, University of New Mexico, Albuquerque, New Mexico 87131-1066, Department of Pharmacology, University of Wisconsin, Madison, Wisconsin 53706, Department of Pharmacology and Molecular Toxicology, University of Massachusetts Medical Center, Worcester, Massachusetts 01655-0126, NIDDK, The National Institutes of Health, Bethesda, Maryland 20892, Naylor DanaHaruhiko Yagi - Department of Medicinal Chemistry & Molecular Pharmacology, Purdue University, West Lafayette, Indiana 47907, Department of Pharmacology & Toxicology, University of New Mexico, Albuquerque, New Mexico 87131-1066, Department of Pharmacology, University of Wisconsin, Madison, Wisconsin 53706, Department of Pharmacology and Molecular Toxicology, University of Massachusetts Medical Center, Worcester, Massachusetts 01655-0126, NIDDK, The National Institutes of Health, Bethesda, Maryland 20892, Naylor DanaDonald M Jerina - Department of Medicinal Chemistry & Molecular Pharmacology, Purdue University, West Lafayette, Indiana 47907, Department of Pharmacology & Toxicology, University of New Mexico, Albuquerque, New Mexico 87131-1066, Department of Pharmacology, University of Wisconsin, Madison, Wisconsin 53706, Department of Pharmacology and Molecular Toxicology, University of Massachusetts Medical Center, Worcester, Massachusetts 01655-0126, NIDDK, The National Institutes of Health, Bethesda, Maryland 20892, Naylor DanaShantu Amin - Department of Medicinal Chemistry & Molecular Pharmacology, Purdue University, West Lafayette, Indiana 47907, Department of Pharmacology & Toxicology, University of New Mexico, Albuquerque, New Mexico 87131-1066, Department of Pharmacology, University of Wisconsin, Madison, Wisconsin 53706, Department of Pharmacology and Molecular Toxicology, University of Massachusetts Medical Center, Worcester, Massachusetts 01655-0126, NIDDK, The National Institutes of Health, Bethesda, Maryland 20892, Naylor DanaSang S Park - Department of Medicinal Chemistry & Molecular Pharmacology, Purdue University, West Lafayette, Indiana 47907, Department of Pharmacology & Toxicology, University of New Mexico, Albuquerque, New Mexico 87131-1066, Department of Pharmacology, University of Wisconsin, Madison, Wisconsin 53706, Department of Pharmacology and Molecular Toxicology, University of Massachusetts Medical Center, Worcester, Massachusetts 01655-0126, NIDDK, The National Institutes of Health, Bethesda, Maryland 20892, Naylor DanaHarry V Gelboin - Department of Medicinal Chemistry & Molecular Pharmacology, Purdue University, West Lafayette, Indiana 47907, Department of Pharmacology & Toxicology, University of New Mexico, Albuquerque, New Mexico 87131-1066, Department of Pharmacology, University of Wisconsin, Madison, Wisconsin 53706, Department of Pharmacology and Molecular Toxicology, University of Massachusetts Medical Center, Worcester, Massachusetts 01655-0126, NIDDK, The National Institutes of Health, Bethesda, Maryland 20892, Naylor DanaWilliam M Baird - Department of Medicinal Chemistry & Molecular Pharmacology, Purdue University, West Lafayette, Indiana 47907, Department of Pharmacology & Toxicology, University of New Mexico, Albuquerque, New Mexico 87131-1066, Department of Pharmacology, University of Wisconsin, Madison, Wisconsin 53706, Department of Pharmacology and Molecular Toxicology, University of Massachusetts Medical Center, Worcester, Massachusetts 01655-0126, NIDDK, The National Institutes of Health, Bethesda, Maryland 20892, Naylor Dana
- Resource Type
- Journal article
- Publication Details
- Chemical research in toxicology, Vol.10(5), pp.609-617
- DOI
- 10.1021/tx960174n
- PMID
- 9168260
- NLM abbreviation
- Chem Res Toxicol
- ISSN
- 0893-228X
- eISSN
- 1520-5010
- Language
- English
- Date published
- 05/01/1997
- Academic Unit
- Community and Behavioral Health
- Record Identifier
- 9984214668602771
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