Cytochromes P4501 (CYP1): Catalytic activities and inducibility by diesel exhaust particle extract and benzo[a]pyrene in intact human lung ex vivo

Iba, Michael M.; Shin, Maria; Caccavale, Robert J.

doi:10.1016/j.tox.2010.04.012

Cited by 12 publications

(25 citation statements)

References 63 publications

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“…Similar to that seen in freshly prepared PBL 21,22,[40][41][42] , the present study has shown that exposure of DEP to IM9 cells significantly increased the mRNA and protein expression of CYP1A1. A similar increase, though of a much higher magnitude, was observed in A549 cells and has also been reported after exposure of DEP or organic extracts of DEP 6,38,40,[43][44][45] .…”

Section: Discussionsupporting

confidence: 87%

Ultrafine Particles of Diesel Exhaust Induces Cytochrome P450 1A1 Mediated Oxidative Stress and DNA Damage in Cultured Blood and Lung Cells

et al. 2016

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Attempts were made to investigate the role of cytochrome P450 1A1 (CYP1A1) on similarities in the generation of reactive oxygen species (ROS) and DNA damage in IM9, a human B lymphoblastic cell line with A549, the human lung adenocarcinoma epithelial cell line on exposure of diesel exhaust particles (DEP). A suspension of ultrafine particles (< 0.2 µM) of DEP (1mg/ml) in DMEM-F12 medium, at a concentration range of 1-100 µg/ml, was added to the cells for 6-48h. Expression studies revealed that DEP induced similar increase in the expression of CYP1A1, generation of ROS and DNA damage in both the cells. Pre-incubation with 3-methylcholanthrene (MC), a CYP1A1 inducer resulted in higher magnitude of induction of CYP1A1, ROS and DNA damage. This synergistic effect was lowered when α-naphthoflavone (α-NF), an inhibitor of CYP1A1 catalysed reactions, was added to these cells. Though the magnitude of alterations was lower in IM9 cells when compared to A549 cells, similarities in the alterations in blood and lungs cells has further suggested that blood lymphocytes can be used as a surrogate to monitor toxicity of vehicular emissions.

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Section: Discussionsupporting

confidence: 87%

Ultrafine Particles of Diesel Exhaust Induces Cytochrome P450 1A1 Mediated Oxidative Stress and DNA Damage in Cultured Blood and Lung Cells

et al. 2016

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“…Although all three share substrates and inhibitors, CYP1A1 and CYP1B1 could be said to have a generally more similar substrate and inhibitor profile than do CYP1A1 and CYP1A2. For example, CYP1A1 and CYP1B1 are better at O-dealkylating ethoxyresorufin than methoxyresorufin, whereas CYP1A2 has the opposite preference (56). Additionally, CYP1A1 and CYP1B1 have more similar oxidation profiles for a variety of substrates (57), as well as inhibition by flavonoids (58) and hydroxystilbenes (59) is important to determine whether the active site topology experimentally defined by CYP1A enzyme structures can be used to rationalize the binding of other known CYP1A ligands.…”

Section: Resultsmentioning

confidence: 99%

“…The CYP1A1 S122T mutation increases the O-dealkylation of both alkoxyresorufins, whereas the CYP1A2 T124S mutation decreases the metabolism of both resorufin substrates (64). CYP1B1 has Ala-133 at the corresponding position, with even lower rates of alkyoxyresorufin metabolism (56). This progression suggests that Thr is optimal in this position with the smaller Ser and Ala reducing O-dealkylation.…”

Section: Resultsmentioning

confidence: 99%

“…Additionally, CYP1A2 metabolizes resveratrol to piceatannol and 3,4,5,4Ј-tetrahydroxystilbene at rates 6-and 5-fold higher than CYP1A1 and CYP1B1, respectively (66). CYP1A1 and CYP1B1 have the same valine (Val-382 and Val-395, respectively) at the position where CYP1A2 has leucine (Leu-382), and both prefer ethoxyresorufin over methoxyresorufin O-dealkylation (56).…”

Section: Resultsmentioning

confidence: 99%

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Human Cytochrome P450 1A1 Structure and Utility in Understanding Drug and Xenobiotic Metabolism

Walsh

Szklarz

Scott

2013

Journal of Biological Chemistry

245

243

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Background: Human cytochrome P450 1A1 (CYP1A1) activates procarcinogens, but the basis of their binding is unknown. Results: A 2.6 Å structure with the inhibitor ␣-naphthoflavone and docking simulations suggest key active site features. Conclusion: CYP1A1 has a planar active site that restricts ligand orientations.Significance: This provides a useful framework for understanding CYP1A1 interactions with a variety of substrates and inhibitors.

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“…CYP1A1-enzymes play a critical role in the metabolic activation of PAHs, and are highly inducible by PAHs via aryl hydrocarbon receptor (AhR)-mediated gene transcription [5]. The potency of DEPs to induce gene expression of CYP1A1 has previously been demonstrated by DEP-extract in human lung samples ex vivo [6] and by DEPs as well as DEP-extracts in human airway epithelial (16HBE) and human macrophage (U937) cell lines [7,8]. …”

Section: Introductionmentioning

confidence: 99%

Diesel exhaust particles induce CYP1A1 and pro-inflammatory responses via differential pathways in human bronchial epithelial cells

et al. 2010

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BackgroundExposure to diesel engine exhaust particles (DEPs) has been associated with several adverse health outcomes in which inflammation seems to play a key role. DEPs contain a range of different inorganic and organic compounds, including polycyclic aromatic hydrocarbons (PAHs). During the metabolic activation of PAHs, CYP1A1 enzymes are known to play a critical role. In the present study we investigated the potential of a characterised sample of DEPs to induce cytotoxicity, to influence the expression of CYP1A1 and inflammation-related genes, and to activate intracellular signalling pathways, in human bronchial epithelial cells. We specifically investigated to what extent DEP-induced expression of interleukin (IL)-6, IL-8 and cyclooxygenase (COX)-2 was regulated differentially from DEP-induced expression of CYP1A1.ResultsThe cytotoxicity of the DEPs was characterised by a marked time- and concentration-dependent increase in necrotic cells at 4 h and above 200 μg/ml (~ 30 μg/cm2). DEP-induced DNA-damage was only apparent at high concentrations (≥ 200 μg/ml). IL-6, IL-8 and COX-2 were the three most up-regulated genes by the DEPs in a screening of 20 selected inflammation-related genes. DEP-induced expression of CYP1A1 was detected at very low concentrations (0.025 μg/ml), compared to the expression of IL-6, IL-8 and COX-2 (50-100 μg/ml). A CYP1A1 inhibitor (α-naphthoflavone), nearly abolished the DEP-induced expression of IL-8 and COX-2. Of the investigated mitogen-activated protein kinases (MAPKs), the DEPs induced activation of p38. A p38 inhibitor (SB202190) strongly reduced DEP-induced expression of IL-6, IL-8 and COX-2, but only moderately affected the expression of CYP1A1. The DEPs also activated the nuclear factor-κB (NF-κB) pathway, and suppression by siRNA tended to reduce the DEP-induced expression of IL-8 and COX-2, but not CYP1A1.ConclusionThe present study indicates that DEPs induce both CYP1A1 and pro-inflammatory responses in vitro, but via differential intracellular pathways. DEP-induced pro-inflammatory responses seem to occur via activation of NF-κB and p38 and are facilitated by CYP1A1. However, the DEP-induced CYP1A1 response does not seem to involve NF-κB and p38 activation. Notably, the present study also indicates that expression of CYP1A1 may represent a particular sensitive biomarker of DEP-exposure.

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Cytochromes P4501 (CYP1): Catalytic activities and inducibility by diesel exhaust particle extract and benzo[a]pyrene in intact human lung ex vivo

Cited by 12 publications

References 63 publications

Ultrafine Particles of Diesel Exhaust Induces Cytochrome P450 1A1 Mediated Oxidative Stress and DNA Damage in Cultured Blood and Lung Cells

Ultrafine Particles of Diesel Exhaust Induces Cytochrome P450 1A1 Mediated Oxidative Stress and DNA Damage in Cultured Blood and Lung Cells

Human Cytochrome P450 1A1 Structure and Utility in Understanding Drug and Xenobiotic Metabolism

Diesel exhaust particles induce CYP1A1 and pro-inflammatory responses via differential pathways in human bronchial epithelial cells

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