Inhibition of CYP1A1-Dependent Activity by the Polynuclear Aromatic Hydrocarbon (PAH) Fluoranthene
Polynuclear aromatic hydrocarbons (PAHs) are ubiquitous environmental contaminants, and recently bioassay-based induction studies have been used to determine exposures to complex mixtures of PAHs. Induction of CYP1A1-dependent activity in H4IIE rat hepatoma cells has been used extensively as a bioas...
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Published in | Biochemical pharmacology Vol. 55; no. 6; pp. 831 - 839 |
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Main Authors | , , , |
Format | Journal Article |
Language | English |
Published |
New York, NY
Elsevier Inc
15.03.1998
Elsevier Science |
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Abstract | Polynuclear aromatic hydrocarbons (PAHs) are ubiquitous environmental contaminants, and recently bioassay-based induction studies have been used to determine exposures to complex mixtures of PAHs. Induction of CYP1A1-dependent activity in H4IIE rat hepatoma cells has been used extensively as a bioassay for halogenated aromatic hydrocarbons and more recently for PAHs. Fluoranthene (FL) is a prevalent PAH contaminant in diverse environmental samples, and FL did not induce CYP1A1-dependent ethoxyresorufin
O-deethylase (EROD) activity significantly in H4IIE cells. However, in cells cotreated with 2 × 10
−5 M FL plus the potent inducers 2,3,7,8-tetrachlorodibenzo-
p-dioxin (TCDD) or benzo[
k]fluoranthene (BkF) (2 × 10
−8 M), there was a significant decrease in EROD activities. Furthermore, treatment of TCDD-induced rat microsomes with FL caused an 80% decrease in EROD activity. Studies showed that FL did not affect induction of CYP1A1 protein or mRNA levels in H4IIE cells, and analysis of enzyme inhibition data using microsomal CYP1A1 indicated that FL noncompetitively inhibited CYP1A1-dependent activity.
32P-Postlabeling revealed no significant FL–DNA adduct formation in H4IIE cells treated with FL. However, in cells cotreated with FL plus BkF or benzo[
a]pyrene (BaP), certain PAH–DNA adducts were induced 2-fold. This study demonstrated that FL is an inhibitor of CYP1A1-dependent enzyme activity in rat hepatoma H4IIE cells and that the genotoxic potency of some carcinogenic PAHs may be modulated by FL in mixtures containing relatively high levels of this compound. |
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AbstractList | Polynuclear aromatic hydrocarbons (PAHs) are ubiquitous environmental contaminants, and recently bioassay-based induction studies have been used to determine exposures to complex mixtures of PAHs. Induction of CYP1A1-dependent activity in H4IIE rat hepatoma cells has been used extensively as a bioassay for halogenated aromatic hydrocarbons and more recently for PAHs. Fluoranthene (FL) is a prevalent PAH contaminant in diverse environmental samples, and FL did not induce CYP1A1-dependent ethoxyresorufin O-deethylase (EROD) activity significantly in H4IIE cells. However, in cells cotreated with 2 x 10(-5) M FL plus the potent inducers 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) or benzo[k]fluoranthene (BkF) (2 x 10(-8) M), there was a significant decrease in EROD activities. Furthermore, treatment of TCDD-induced rat microsomes with FL caused an 80% decrease in EROD activity. Studies showed that FL did not affect induction of CYP1A1 protein or mRNA levels in H4IIE cells, and analysis of enzyme inhibition data using microsomal CYP1A1 indicated that FL noncompetitively inhibited CYP1A1-dependent activity. 32P-Postlabeling revealed no significant FL-DNA adduct formation in H4IIE cells treated with FL. However, in cells cotreated with FL plus BkF or benzo[a]pyrene (BaP), certain PAH-DNA adducts were induced 2-fold. This study demonstrated that FL is an inhibitor of CYP1A1-dependent enzyme activity in rat hepatoma H4IIE cells and that the genotoxic potency of some carcinogenic PAHs may be modulated by FL in mixtures containing relatively high levels of this compound. Polynuclear aromatic hydrocarbons (PAHs) are ubiquitous environmental contaminants, and recently bioassay-based induction studies have been used to determine exposures to complex mixtures of PAHs. Induction of CYP1A1-dependent activity in H4IIE rat hepatoma cells has been used extensively as a bioassay for halogenated aromatic hydrocarbons and more recently for PAHs. Fluoranthene (FL) is a prevalent PAH contaminant in diverse environmental samples, and FL did not induce CYP1A1-dependent ethoxyresorufin O-deethylase (EROD) activity significantly in H4IIE cells. However, in cells cotreated with 2 × 10 −5 M FL plus the potent inducers 2,3,7,8-tetrachlorodibenzo- p-dioxin (TCDD) or benzo[ k]fluoranthene (BkF) (2 × 10 −8 M), there was a significant decrease in EROD activities. Furthermore, treatment of TCDD-induced rat microsomes with FL caused an 80% decrease in EROD activity. Studies showed that FL did not affect induction of CYP1A1 protein or mRNA levels in H4IIE cells, and analysis of enzyme inhibition data using microsomal CYP1A1 indicated that FL noncompetitively inhibited CYP1A1-dependent activity. 32P-Postlabeling revealed no significant FL–DNA adduct formation in H4IIE cells treated with FL. However, in cells cotreated with FL plus BkF or benzo[ a]pyrene (BaP), certain PAH–DNA adducts were induced 2-fold. This study demonstrated that FL is an inhibitor of CYP1A1-dependent enzyme activity in rat hepatoma H4IIE cells and that the genotoxic potency of some carcinogenic PAHs may be modulated by FL in mixtures containing relatively high levels of this compound. |
Author | Willett, Kristine L Zhou, Guo-Dong Safe, Stephen H Randerath, Kurt |
Author_xml | – sequence: 1 givenname: Kristine L surname: Willett fullname: Willett, Kristine L organization: Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, TX 77843-4466, USA – sequence: 2 givenname: Kurt surname: Randerath fullname: Randerath, Kurt organization: Division of Toxicology, Baylor College of Medicine, Texas Medical Center, Houston, TX 77030, USA – sequence: 3 givenname: Guo-Dong surname: Zhou fullname: Zhou, Guo-Dong organization: Division of Toxicology, Baylor College of Medicine, Texas Medical Center, Houston, TX 77030, USA – sequence: 4 givenname: Stephen H surname: Safe fullname: Safe, Stephen H organization: Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, TX 77843-4466, USA |
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Keywords | H4IIE cells CYP1A1 Ah receptor PAHs fluoranthene DNA adducts Rat Digestive system Toxicity Cytochrome P450 Liver Rodentia Enzyme inhibitor Microsome Halocarbon Carcinogen Vertebrata Mammalia Animal DNA Fluoranthene |
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Snippet | Polynuclear aromatic hydrocarbons (PAHs) are ubiquitous environmental contaminants, and recently bioassay-based induction studies have been used to determine... |
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SubjectTerms | Ah receptor Animals Biological and medical sciences Biological Assay Carcinogenesis, carcinogens and anticarcinogens Chemical agents Chemical and industrial products toxicology. Toxic occupational diseases CYP1A1 Cytochrome P-450 CYP1A1 - antagonists & inhibitors Cytochrome P-450 CYP1A1 - biosynthesis DNA adducts DNA Adducts - isolation & purification DNA, Neoplasm - isolation & purification Enzyme Induction Enzyme Inhibitors - pharmacology Female fluoranthene Fluorenes - pharmacology H4IIE cells Linear Models Medical sciences Microsomes, Liver - enzymology PAHs Rats Rats, Sprague-Dawley Toxicology Tumor Cells, Cultured Tumors Various organic compounds |
Title | Inhibition of CYP1A1-Dependent Activity by the Polynuclear Aromatic Hydrocarbon (PAH) Fluoranthene |
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