Polycyclic aromatic hydrocarbons (PAHs) are present in cigarette smoke, particulate matter, and in charcoal broiled meats. The cytochrome P450 (CYP)1A enzymes play pivotal roles in the activation of PAHs to metabolites that are interact covalently with DNA, a critical event in the initiation of carcinogenesis. The central hypothesis of this application is that CYP1A1 and CYP1A2 enzymes play reciprocal roles in PAH-mediated carcinogenesis, and that a CYP1A2-dependent MC metabolite(s) contributes to the formation of sequence- specific DNA adducts on the regulatory regions of the CYP1A1 promoter [e.g., AHR response elements (AHREs)], leading to a novel mechanism by which MC-DNA adduct(s) will suppress CYP1A1 gene expression. The following Specific Aims are proposed. 1. To determine the mechanistic role of CYP1A1 and 1A2 enzymes in PAH-mediated lung cancers.
This aim has two sub-aims: (i) To test the hypothesis that mice lacking the gene for Cyp1a2 will be more susceptible, and those lacking the gene for Cyp1a1 will be less susceptible to PAH-induced lung carcinogenesis and tumorigenesis than similarly exposed WT mice. (ii) To test the hypothesis that humanized CYP1A1 mice will be more susceptible to lung carcinogenesis and tumorigenesis than WT mice, while humanized CYP1A2 mice will be less susceptible. 2. To determine the molecular mechanisms of sustained induction and suppression of hepatic and pulmonary CYP1A1 by MC in vivo.
This aim has two sub-aims: (i) To test the hypothesis that hepatic CYP1A2 mechanistically contributes to the suppression of sustained hepatic and pulmonary CYP1A1 by MC. (ii) To test the hypothesis that MC elicits persistent human CYP1A1 induction by sustained transcriptional activation of the corresponding promoter, and that hepatic CYP1A2 will suppress persistent induction of hepatic and pulmonary CYP1A1 expression in transgenic humanized mice expressing the human CYP1A1 (hCYP1A1-luc or hCYP1A1-GFP) on Cyp1a1- or Cyp1a1/1a2-null backgrounds. 3. To determine the molecular mechanisms of suppression of pulmonary CYP1A1 induction. We will test the hypothesis that CYP1A2-derived MC metabolites contribute to suppression of pulmonary cells via sequence-specific DNA adducts on the AHREs of the CYP1A1 promoter.
This aim has two sub-aims. (i) To test the hypothesis that cells transfected with plasmids containing CYP1A2-derived DNA adducts will display suppression of CYP1A1 transcription in human pulmonary cells (e.g., A549, BEAS-2B) in vitro. (ii) To test the hypothesis that exposure of human lung cells overexpressing CYP1A2 to MC will display attenuation of sustained CYP1A1 induction. The long-term objectives are to: (i) define the molecular mechanisms of regulation of CYP1A1 gene expression by PAHs, (ii) elucidate the possible role of gene- specific DNA adducts in molecular regulation of CYP1A1, and (iii) develop rational strategies for the prevention/treatment of human cancers caused by environmental chemicals.

Public Health Relevance

Polycyclic aromatic hydrocarbons (PAHs) are present in cigarette smoke, particulate matter, and in charcoal broiled meats. The proposed studies would lead to development of rational strategies for the chemoprevention and/or chemotherapy of lung cancers caused by environmental chemicals in humans. The long-term objectives are to: (i) define the molecular mechanisms of regulation of cytochrome P450 (CYP)1A1 gene expression by PAHs, (ii) elucidate the possible role of gene-specific DNA adducts in molecular regulation of drug metabolizing enzymes, and (iii) develop rational strategies for the prevention/treatment of human cancers caused by environmental chemicals.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES009132-11
Application #
8435452
Study Section
Xenobiotic and Nutrient Disposition and Action Study Section (XNDA)
Program Officer
Carlin, Danielle J
Project Start
1998-08-01
Project End
2016-02-29
Budget Start
2013-03-01
Budget End
2014-02-28
Support Year
11
Fiscal Year
2013
Total Cost
$346,847
Indirect Cost
$126,347
Name
Baylor College of Medicine
Department
Pediatrics
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030
Ghose, Romi; Mallick, Pankajini; Taneja, Guncha et al. (2016) In Vitro Approaches to Study Regulation of Hepatic Cytochrome P450 (CYP) 3A Expression by Paclitaxel and Rifampicin. Methods Mol Biol 1395:55-68
Dinu, Daniela; Chu, Chun; Veith, Alex et al. (2016) Mechanistic role of cytochrome P450 (CYP)1B1 in oxygen-mediated toxicity in pulmonary cells: A novel target for prevention of hyperoxic lung injury. Biochem Biophys Res Commun 476:346-51
Shah, Pranav; Omoluabi, Ozozoma; Moorthy, Bhagavatula et al. (2016) Role of Adaptor Protein Toll-Like Interleukin Domain Containing Adaptor Inducing Interferon β in Toll-Like Receptor 3- and 4-Mediated Regulation of Hepatic Drug Metabolizing Enzyme and Transporter Genes. Drug Metab Dispos 44:61-7
Patel, Ananddeep; Zhang, Shaojie; Shrestha, Amrit Kumar et al. (2016) Omeprazole induces heme oxygenase-1 in fetal human pulmonary microvascular endothelial cells via hydrogen peroxide-independent Nrf2 signaling pathway. Toxicol Appl Pharmacol 311:26-33
Lingappan, Krithika; Jiang, Weiwu; Wang, Lihua et al. (2015) Sex-specific differences in hyperoxic lung injury in mice: role of cytochrome P450 (CYP)1A. Toxicology 331:14-23
Zhang, Shaojie; Patel, Ananddeep; Moorthy, Bhagavatula et al. (2015) Adrenomedullin deficiency potentiates hyperoxic injury in fetal human pulmonary microvascular endothelial cells. Biochem Biophys Res Commun 464:1048-53
Wang, Lihua; Lingappan, Krithika; Jiang, Weiwu et al. (2015) Disruption of cytochrome P4501A2 in mice leads to increased susceptibility to hyperoxic lung injury. Free Radic Biol Med 82:147-59
Zhang, Shaojie; Patel, Ananddeep; Chu, Chun et al. (2015) Aryl hydrocarbon receptor is necessary to protect fetal human pulmonary microvascular endothelial cells against hyperoxic injury: Mechanistic roles of antioxidant enzymes and RelB. Toxicol Appl Pharmacol 286:92-101
Lingappan, Krithika; Moorthy, Bhagavatula (2015) Can maternal DHA supplementation offer long-term protection against neonatal hyperoxic lung injury? Am J Physiol Lung Cell Mol Physiol 309:L1383-6
Patel, Ananddeep; Zhang, Shaojie; Moorthy, Bhagavatula et al. (2015) Omeprazole does not Potentiate Acute Oxygen Toxicity in Fetal Human Pulmonary Microvascular Endothelial Cells Exposed to Hyperoxia. Pharm Anal Acta 6:

Showing the most recent 10 out of 57 publications