Metabolic Enzyme Induction by HepG2 Cells Exposed to Oxygenated and Nonoxygenated Polycyclic Aromatic Hydrocarbons

Misaki, Kentaro; Matsui, Saburo; Matsuda, Tomonari

doi:10.1021/tx060197u

Cited by 32 publications

(28 citation statements)

References 40 publications

(78 reference statements)

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“…The data are expressed the means 6 S.D. causes a significant upregulation of CYP1A1/2 mRNAs expression [Misaki et al, 2007;Abdelhamid et al, 2010;Zhang et al, 2011]. Consistent with these results, DiMeDBC and mainly N-MeDBC increased substantially the CYP1A1/2 mRNA levels in HepG2 cells.…”

Section: Discussionsupporting

confidence: 82%

Genotoxicity of 7H-dibenzo[c,g]carbazole and its tissue-specific derivatives in human hepatoma HepG2 cells is related to CYP1A1/1A2 expression

Gábelová

Valovičová

Mesárošová

et al. 2011

Environ. Mol. Mutagen.

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The goal of this study was to investigate the genotoxicity of 7H-dibenzo[c,g]carbazole (DBC), a ubiquitous environmental pollutant, and its methyl derivatives, 5,9-dimethylDBC (DiMeDBC), a strict hepatocarcinogen, and N-methylDBC (N-MeDBC), a specific sarcomagen in human hepatoma HepG2 cells, and to infer potential mechanisms underlying the biological activity of particular carcinogen. All dibenzocarbazoles, regardless the tissue specificity, induced significant DNA strand break levels and micronuclei in HepG2 cells; though a mitotic spindle dysfunction rather than a chromosome breakage was implicated in N-MeDBC-mediated micronucleus formation. While DBC and N-MeDBC produced stable DNA adducts followed with p53 protein phosphorylation at Ser-15, DiMeDBC failed. A significant increase in DNA strand breaks following incubation of exposed cells with a repair-specific endonuclease (Fpg protein) suggested that either oxidative DNA damage or unstable DNA-adducts might underlie DiMeDBC genotoxicity in human hepatoma cells. DiMeDBC and N-MeDBC increased substantially also the amount of CYP1A1/2 expression in HepG2 cells. Pretreatment of cells with substances affecting AhR-mediated CYP1A family of enzymes expression; however, diminished DiMeDBC and N-MeDBC genotoxicity. Our data clearly demonstrated differences in the mechanisms involved in the biological activity of DiMeDBC and N-MeDBC in human hepatoma cells; the genotoxicity of these DBC derivatives is closely related to CYP1A1/2 expression.

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Section: Discussionsupporting

confidence: 82%

Genotoxicity of 7H-dibenzo[c,g]carbazole and its tissue-specific derivatives in human hepatoma HepG2 cells is related to CYP1A1/1A2 expression

Gábelová

Valovičová

Mesárošová

et al. 2011

Environ. Mol. Mutagen.

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“…Induction equivalency factor (IEF) is the ratio of EC TCDD25 of test compound relative to benzo[ a ]pyrene (B[ a ]P). Data regarding CYP1A1 mRNA induction are from Misaki et al [25]. PhO = phenalenone; BAO = 7 H ‐benz[ de ]anthracen‐7‐one; FlO = fluorenone; AO = anthrone; XO = xanthone; TXO = thioxanthone; B[ a ]FO = 11 H ‐benzo[ a ]fluoren‐11‐one; B[ a ]FO = 11 H ‐benzo[ b ]fluoren‐11‐one; B[ c ]FO = 7 H ‐benzo[ c ]fluoren‐7‐one; CPPO = cyclopenta[ cd ]pyren‐3[4 H ]‐one; BPO = 6 H ‐benzo[ de ]pyren‐6‐one; AQ = anthraquinone; PhQ = phenanthrenequinone; ChQ = 1,4‐chrysenequinone; BAQ = 7,12‐benz[ a ]anthracenequinone; NCQ = 5,12‐naphthacenequinone; Alz = alizarin; PCQ = pentacenequinone; NA = 1,8‐naphthalic anhydride; β‐NF = β‐naphthoflavone; Nph = naphthalene; ANthyl = acenaphthylene; ANthe = acenaphthene; Fl = fluorene; Ant = anthracene; Ph = phenanthrene; FA = fluoranthene; Py = pyrene; B[ a ]A = benz[ a ]anthracene; Chr = chrysene; TPh = triphenylene; B[ b ]F = benzo[ b ]fluorene; B[ b ]FA = benzo[ b ]fluoranthene; B[ k ]FA = benzo[ k ]fluoranthene; B[ a ]P = benzo[ a ]pyrene; DB[ a,h ]A = dibenz[ a,h ]anthracene; DB[ a,c ]A = dibenz[ a,c ]anthracene; 3‐MC = 3‐methylcholanthrene; IdP = indeno[1,2,3‐ cd ]pyrene; B[ ghi ]Pe = benzo[ ghi ]perylene; N[ a ]P = naphtho[2,3‐ a ]pyrene; U = <25% of TCDD max; NI = not induced.…”

Section: Resultsmentioning

confidence: 99%

Aryl hydrocarbon receptor ligand activity of polycyclic aromatic ketones and polycyclic aromatic quinones

Misaki

Kawami

Tanaka

et al. 2007

Enviro Toxic and Chemistry

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Polycyclic aromatic ketones (PAKs) and polycyclic aromatic quinones (PAQs) are oxygenated polycyclic aromatic hydrocarbons (PAHs), and reports about the aryl hydrocarbon receptor (AhR) ligand activities of these compounds are few. In this study, activation of AhR by 41 polycyclic aromatic compounds (PACs), focusing especially on PAKs and PAQs, was determined by measuring beta-galactosidase activity from a reporter plasmid in yeast engineered to express human AhR and the AhR nuclear translocator proteins and by measuring luciferase activity from mouse hepatoma (H1L1) cells (chemical-activated luciferase expression [CALUX] assay). The PACs used in these experiments included 11 PAKs, seven PAQs, and 21 PAHs. In this study, the PAKs 11H-benzo[a]fluoren-11-one (B[a]FO), 11H-benzo[b]fluoren-11-one (B[b]FO) and 7H-benzo[c]fluoren-7-one and the PAQs 5,12-naphthacenequinone, 1,4-chrysenequinone, and 7,12-benz[a]anthracenequinone showed high AhR activities in H1L1 cells, although these values were not as high as that for benzo[a]pyrene (B[a]P). These PAKs and PAQs showed significantly stronger activities in yeast cells relative to B[a]P. It was predicted that PAKs such as B[a]FO and B[b]FO occupied 0.06% to 1.3% of the total induction equivalents, and each contribution matched the contribution of PAHs such as B[a]P, chrysene, and benz[a]anthracene in gasoline exhaust particulates and airborne particulates using data of CALUX assay.

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“…16) It has been reported that oxygenated PAHs which are polar compounds contribute more greatly than PAHs to the AhR activity of environmental air samples. 17,18) PAH ketones and quinones originating from gasoline and diesel engine exhausts are present at comparatively high concentrations (e.g., 11H-benzo[a]fluoren-11-one: 1.026 ± 0.037 ng/m 3 , 5) comparing with other detected compounds, and 9,10-PQ also exist at high concentration in ambient air. 6) The high concentration of PAH ketones and quinones in the atmosphere suggest that large amount of human exposure to these compounds through respiration.…”

Section: Discussionmentioning

confidence: 99%

Evaluation of Toxic Activities of Polycyclic Aromatic Hydrocarbon Derivatives Using In Vitro Bioassays

Bekki

Takigami

Suzuki

et al. 2009

JOURNAL OF HEALTH SCIENCE

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Several polycyclic aromatic hydrocarbons and nitrated polycyclic aromatic hydrocarbons (PAHs/NPAHs) such as benzo [a]pyrene and 1-nitropyrene are mutagens and/or carcinogens. These compounds secondarily generate PAH hydroxides, ketones, and quinones through atmospheric and metabolic reactions. The health effects of these compounds is now an important social concern. For example, lung cancer, bronchitis, whistling and so on. In this work, we evaluated toxicities of 25 PAH derivatives (hydroxides, ketones and quinones) in terms of aryl hydrocarbon receptor (AhR) binding and thyroid hormone-related endpoints using three in vitro bioassays: dioxinresponsive chemical-activated luciferase gene expression (DR-CALUX), thyroid receptor β chemical-activated luciferase gene expression (TRβ-CALUX), and competitive human transthyretin-binding (TTR-binding) assays. Eleven of the 25 PAH derivatives had AhR agonist activity, six had AhR antagonist activity and seven had TRpotentiation activity in the TR-CALUX. Furthermore, PAH quinones and hydroxides had strong TTR-binding activity. 3,4-Dihydrobenz[a]anthracen-1(2 H)-one had the strongest agonist activity (EC 20 : 0.4 µM) as determined by DR-CALUX. PAH ketones showed stronger activity than the control and significant difference by statistical analysis. Benzo[c]phenanthrene-[1,4]-quinone was the most TTR-active compound (IC 50 : 2.5 µM). Both PAH ketones and quinones, which have functional groups with low polarity, had significant activities in all tested assays. These in vitro results suggest that PAH derivatives might have various toxic activities in animals. For estimating the health effects and accessing the environmental risks of PAHs, further studies on the toxicity mechanisms are necessary.

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Metabolic Enzyme Induction by HepG2 Cells Exposed to Oxygenated and Nonoxygenated Polycyclic Aromatic Hydrocarbons

Cited by 32 publications

References 40 publications

Genotoxicity of 7H-dibenzo[c,g]carbazole and its tissue-specific derivatives in human hepatoma HepG2 cells is related to CYP1A1/1A2 expression

Genotoxicity of 7H-dibenzo[c,g]carbazole and its tissue-specific derivatives in human hepatoma HepG2 cells is related to CYP1A1/1A2 expression

Aryl hydrocarbon receptor ligand activity of polycyclic aromatic ketones and polycyclic aromatic quinones

Evaluation of Toxic Activities of Polycyclic Aromatic Hydrocarbon Derivatives Using In Vitro Bioassays

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