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1.
Int J Cancer ; 120(6): 1161-8, 2007 Mar 15.
Article in English | MEDLINE | ID: mdl-17187366

ABSTRACT

A complex mixture of polycyclic aromatic hydrocarbons (PAH) extracted from coal tar, the Standard Reference Material (SRM) 1597, was recently shown to decrease the levels of DNA binding of the 2 strong carcinogens benzo[a]pyrene (BP) and dibenzo[a,l]pyrene (DBP) in the human mammary carcinoma-derived cell line MCF-7 (Mahadevan et al., Chem Res Toxicol 2005;18:224-231). The present study was designed to further elucidate the biochemical mechanisms involved in this inhibition process. We examined the effects of SRM 1597 on the metabolic activation of BP and DBP toward DNA-binding derivatives in Chinese hamster cells expressing either human cytochrome P450 (CYP) 1A1 or CYP1B1. SRM 1597 inhibited BP-DNA adduct formation through the entire exposure time in cells expressing human CYP1A1, while it significantly inhibited adduct formation only up to 48 hr when co-treated with DBP. Conversely, human CYP1B1-expressing cells were unable to catalyze PAH-DNA adduct formation on treatment with SRM 1597 alone, and on co-treatment with BP or DBP. The data obtained from biochemical experiments revealed that SRM 1597 competitively inhibited the activity of both human enzymes as analyzed by 7-ethoxyresorufin O-deethylation assays. While the Michaelis-Menten constant (K(M)) was <0.4 microM in the absence of SRM 1597, this value increased up to 1.12 (CYP1A1) or 4.45 microM (CYP1B1) in the presence of 0.1 microg/ml SRM 1597. Hence the inhibitory effects of the complex mixture on human CYP1B1 were much stronger when compared to human CYP1A1. Taken together, the decreases in PAH-DNA adduct formation on co-treatment with SRM 1597 revealed inhibitory effects on the CYP enzymes that convert carcinogenic PAH into DNA-binding metabolites. The implications for the tumorigenicity of complex environmental PAH mixtures are discussed.


Subject(s)
Aryl Hydrocarbon Hydroxylases/antagonists & inhibitors , Carcinogens/antagonists & inhibitors , Coal Tar/chemistry , Cytochrome P-450 CYP1A1/antagonists & inhibitors , Polycyclic Aromatic Hydrocarbons/pharmacology , Aryl Hydrocarbon Hydroxylases/drug effects , Benzo(a)pyrene/antagonists & inhibitors , Benzo(a)pyrene/toxicity , Benzopyrenes/toxicity , Carcinogens/toxicity , Complex Mixtures/isolation & purification , Complex Mixtures/pharmacology , Complex Mixtures/standards , Cytochrome P-450 CYP1A1/drug effects , Cytochrome P-450 CYP1B1 , DNA/drug effects , DNA/metabolism , DNA Adducts/analysis , Humans , Polycyclic Aromatic Hydrocarbons/isolation & purification , Polycyclic Aromatic Hydrocarbons/standards , Tumor Cells, Cultured
2.
Chem Res Toxicol ; 18(2): 224-31, 2005 Feb.
Article in English | MEDLINE | ID: mdl-15720126

ABSTRACT

A complex mixture of polycyclic aromatic hydrocarbons (PAH) extracted from coal tar, standard reference material (SRM) 1597, has been shown to initiate tumor formation in mouse initiation-promotion assays in our laboratory [(2001) Carcinogenesis 22 (7), 1077-1086]. To determine the effects of SRM 1597 on PAH activation in human cells, we investigated the PAH-DNA adduct formation in the human mammary carcinoma-derived cell line MCF-7. We examined the effects of SRM 1597 on the metabolic activation to DNA binding derivatives of two carcinogenic PAHs, the bay region containing benzo[a]pyrene (B[a]P) and the more carcinogenic fjord region containing dibenzo[a,l]pyrene (DB[a,l]P). PAH-DNA adduct analysis by 33P-postlabeling and reversed phase high-performance liquid chromatography revealed a significant decrease in the levels of both B[a]P and DB[a,l]P DNA adduct formation on cotreatment with SRM 1597 in comparison to cells exposed to B[a]P or DB[a,l]P alone. However, the inhibition of PAH-DNA adduct formation only occurred within the first 48 h of exposure in cells cotreated with SRM 1597 and B[a]P. In contrast, SRM 1597 significantly inhibited the level of DB[a,l]P DNA adducts throughout the 120 h of exposure. Induction of human cytochrome P450 (P450) enzymes 1A1 and P4501B1 on treatment with SRM 1597 was observed by immunoblots. These results suggest that the important factors in determining the carcinogenic activity of PAH within a complex mixture would depend on the ability of other components of the mixture to promote or inhibit the activation of carcinogenic PAH by the induction of P450 enzymes followed by the formation of DNA adducts.


Subject(s)
Carcinogens/pharmacokinetics , Coal Tar/chemistry , Coal Tar/standards , Polycyclic Aromatic Hydrocarbons/pharmacokinetics , Aryl Hydrocarbon Hydroxylases/biosynthesis , Aryl Hydrocarbon Hydroxylases/drug effects , Biotransformation , Carcinogens/chemistry , Carcinogens/toxicity , Cell Line, Tumor , Cells, Cultured , Cytochrome P-450 CYP1A1/biosynthesis , Cytochrome P-450 CYP1A1/drug effects , Cytochrome P-450 CYP1B1 , DNA/drug effects , DNA/metabolism , DNA Adducts/chemistry , Humans , Polycyclic Aromatic Hydrocarbons/chemistry , Polycyclic Aromatic Hydrocarbons/toxicity , Time Factors
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