Naphthalene (NA) is a ubiquitous pollutant to which humans are widely exposed. NA causes tumors in rats and mice, and has been classified as a Possible Human Carcinogen. The mechanism of NA carcinogenicity is believed to involve repeated cycles of NA-induced acute lung injury and repair. A prerequisite for NA cytotoxicity is its bioactivation by cytochrome P450 (CYP) enzymes;the reactive metabolites formed, which derive from the NA-epoxide (NA-O), can deplete cellular glutathione (GSH) and, at higher concentrations, bind covalently to tissue proteins. NA-O can be produced by both lung and liver. The major enzymes responsible for NA bioactivation in the mouse include CYP2A5 and CYP2F2;Cyp2f2-null mice are highly resistant to NA lung toxicity, whereas Cyp2a5-null mice are partially protected against NA nasal toxicity. Both human lung and human liver are capable of metabolizing NA, although large interindividual variations exist in the rates of microsomal NA metabolism and bioactivation. However, the roles of human CYP2A13 and CYP2F1 (orthologs of mouse CYP2A5 and CYP2F2, respectively) in NA bioactivation are not well understood, and the potential impact of variations in hepatic P450 function on an individual's risks of developing NA- mediated lung toxicity remains undefined. The objectives of this application are to define the role of CYP2A13 and CYP2F1 in NA bioactivation and toxicity in the lungs of CYP2A13/2F1-humanized mice;identify human lung regions that are enriched in CYP2A13/2F1 expression;and determine whether P450- mediated NA bioactivation and/or detoxification in the liver could contribute to, or otherwise influence, NA lung toxicity. The central hypothesis is that NA has the potential to cause lung toxicity in humans and that the metabolism of NA in both lung and liver influence the outcome on an individual basis. This hypothesis will be tested in two specific aims that will 1) define the role of CYP2A13 and CYP2F1 in NA bioactivation and toxicity in the lung;2) define whether hepatic NA metabolism could influence the risks of NA lung toxicity. We will employ a combination of in vivo and in vitro approaches, and utilize a number of genetically modified mouse models, as well as human tissues and cells, to address the specific aims. The long-term goal of these studies is to define the metabolic mechanisms that influence NA-mediated lung toxicity in experimental animals and humans.

Public Health Relevance

Naphthalene, a lung toxicant and possible human carcinogen, is a ubiquitous environmental pollutant with widespread human exposure. The proposed studies will define the key events that influence the risks of naphthalene-mediated lung toxicity in exposed individuals, and aid in the identification of at-risk individuals for intervention and in te design of effective approaches to disease prevention.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
7R01ES020867-02
Application #
8840377
Study Section
Special Emphasis Panel (ZRG1-DKUS-C (90))
Program Officer
Nadadur, Srikanth
Project Start
2013-08-20
Project End
2018-04-30
Budget Start
2014-05-01
Budget End
2015-04-30
Support Year
2
Fiscal Year
2014
Total Cost
$359,167
Indirect Cost
$64,506
Name
State University of New York at Albany
Department
Public Health & Prev Medicine
Type
Schools of Public Health
DUNS #
152652822
City
Albany
State
NY
Country
United States
Zip Code
12222
Van Winkle, Laura S; Kelty, Jacklyn S; Plopper, Charles G (2017) Preparation of Specific Compartments of the Lungs for Pathologic and Biochemical Analysis of Toxicologic Responses. Curr Protoc Toxicol 71:24.5.1-24.5.26
Li, Lei; Carratt, Sarah; Hartog, Matthew et al. (2017) Human CYP2A13 and CYP2F1 Mediate Naphthalene Toxicity in the Lung and Nasal Mucosa of CYP2A13/2F1-Humanized Mice. Environ Health Perspect 125:067004
Li, Lei; Bao, Xiaochen; Zhang, Qing-Yu et al. (2017) Role of CYP2B in Phenobarbital-Induced Hepatocyte Proliferation in Mice. Drug Metab Dispos 45:977-981
Sheng, Jonathan; Wang, Yi; Turesky, Robert J et al. (2016) Novel Transgenic Mouse Model for Studying Human Serum Albumin as a Biomarker of Carcinogenic Exposure. Chem Res Toxicol 29:797-809
Carratt, S A; Morin, D; Buckpitt, A R et al. (2016) Naphthalene cytotoxicity in microsomal epoxide hydrolase deficient mice. Toxicol Lett 246:35-41
Xie, Fang; Ding, Xinxin; Zhang, Qing-Yu (2016) An update on the role of intestinal cytochrome P450 enzymes in drug disposition. Acta Pharm Sin B 6:374-383
Pinkerton, Kent E; Harbaugh, Mary; Han, MeiLan K et al. (2015) Women and Lung Disease. Sex Differences and Global Health Disparities. Am J Respir Crit Care Med 192:11-6
Kültz, Dietmar; Li, Johnathon; Sacchi, Romina et al. (2015) Alterations in the proteome of the respiratory tract in response to single and multiple exposures to naphthalene. Proteomics 15:2655-68
Liu, Zhihua; Li, Lei; Wu, Hong et al. (2015) Characterization of CYP2B6 in a CYP2B6-humanized mouse model: inducibility in the liver by phenobarbital and dexamethasone and role in nicotine metabolism in vivo. Drug Metab Dispos 43:208-16
Turesky, Robert J; Konorev, Dmitri; Fan, Xiaoyu et al. (2015) Effect of Cytochrome P450 Reductase Deficiency on 2-Amino-9H-pyrido[2,3-b]indole Metabolism and DNA Adduct Formation in Liver and Extrahepatic Tissues of Mice. Chem Res Toxicol 28:2400-10

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