Naphthalene (NA) is a ubiquitous pollutant to which humans are widely exposed. NA causes nasal and lung toxicities, including tumors, in adult rats and mice and has been classified as a possible human carcinogen. The mechanism of NA carcinogenicity, which may involve both genotoxic and non-genotoxic events, is not clear. A prerequisite for NA cytotoxicity is bioactivation by cytochrome P450 (CYP) enzymes. The reactive metabolites formed, which derive from the NA-epoxide (NAO), can deplete cellular glutathione and bind covalently to proteins. Research in the current funding cycle, which was focused on NA bioactivation and acute lung toxicity, provided compelling evidence for the ability of human CYP2A13 and 2F1 to mediate NA?s lung toxicity in vivo in a humanized mouse model, and insights on the interplay between systemic disposition and target tissue bioactivation of inhaled NA and its impact on NA?s airway toxicity. Initial novel evidence was also obtained for the ability of NA to produce stable DNA adducts ex vivo, and for a possible role of systemically generated NA metabolites in lung toxicity in vivo. In the proposed studies for the next funding cycle, we will continue to study the metabolic mechanisms of NA lung toxicity by: identifying liver-generated NA metabolites that contribute to lung toxicity in vivo (Aim 1), determining the ability of human CYP2A6 expressed in the mouse liver to mediate airway toxicity of inhaled NA (Aim 2), and identifying the stable NA- DNA adducts in the lung and dissecting metabolic mechanisms of their formation (Aim 3). The central hypothesis is that NA has the potential to cause both cytotoxicity and genotoxicity in human lung, and that the metabolism of NA in both lung and liver influences the toxic outcome on an individual basis. We will employ a combination of in vivo, ex vivo, and in vitro approaches, and utilize novel genetically modified or humanized mouse models, as well as human lung cells and liver microsomes, 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. The outcome is expected to improve assessment of human lung disease risks from exposures to NA and other related chemicals.

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 the 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 #
2R01ES020867-08
Application #
9765706
Study Section
Xenobiotic and Nutrient Disposition and Action Study Section (XNDA)
Program Officer
Carlin, Danielle J
Project Start
2013-08-20
Project End
2024-04-30
Budget Start
2019-05-01
Budget End
2020-04-30
Support Year
8
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Arizona
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
806345617
City
Tucson
State
AZ
Country
United States
Zip Code
85721
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
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
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
K├╝ltz, 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

Showing the most recent 10 out of 11 publications