Lung cancer is the leading cause of cancer-related death in the U.S., and tobacco smoke (TS) exposure is the most important contributing factor. However, while much has been learned about the tumorigenic effects and the underlying mechanisms of many individual tobacco carcinogens, relatively little is known about the mechanisms of carcinogenesis induced by TS, the actual complex environmental mixture that many people are exposed to on a daily basis. The in vivo contribution of specific carcinogens and their bioactivation to TS-induced lung tumorigenesis, or to TS-induced pathologic changes that precede carcinogenesis, such as lung inflammation, is largely unknown; but such knowledge is critical for designing effective chemoprevention for TS-induced lung toxicity and for assessing the safety of new tobacco products. The long-term objective of this grant has been to determine the role of respiratory tract cytochrome P450 (P450 or CYP) enzymes in the metabolic activation and toxicity of environmental chemicals, with a focus on CYP2A13, a human enzyme selectively expressed in the respiratory tract. Our central hypothesis is that CYP2A13 plays a vital role in tobacco-related lung carcinogenesis. The ability of CYP2A13 to mediate lung tumorigenesis induced by a major tobacco carcinogen, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), is now well-documented, e.g., by our studies of CYP2A13-humanized mice. CYP2A13 also bioactivates many other TS toxicants/carcinogens. Epidemiologic studies of the CYP2A13*2 allele further support an important role of CYP2A13 in lung cancer risk in human smokers. A logical next step is to directly determine the role of CYP2A13 in TS-induced lung tumorigenesis. Thus, we will determine the in vivo role of human CYP2A13 and other P450 enzymes encoded by the mouse and human CYP2ABFS gene cluster in environmental tobacco smoke (ETS)-induced lung tumorigenesis (Aim 1) and lung inflammation (Aim 2); the latter is linked with both tumor initiation and tumor promotion.
In Aim 1, we will test the hypothesis that deletion of mouse Cyp2abfs and addition of human CYP2A13 will lead to corresponding changes in the extent of lung tumorigenesis and the levels of O6-methylguanine (O6-mG) DNA adduct in the lung, in mice exposed chronically to ETS.
In Aim 2, we will test the hypothesis that unique subsets of ETS constituents, which depend on CYP2A/B/F/S enzymes for bioactivation, enable ETS to cause lung inflammation in vivo. Our goal is to establish CYP2A13 as a valid genetic marker for lung cancer risk assessment and a logical molecular target for chemoprevention.

Public Health Relevance

A better understanding of the metabolic mechanisms underlying tobacco smoke-induced lung cancer, which is the leading cause of cancer-related death in the U.S., would increase confidence in assessing the risks of developing lung cancer among first-hand and second-hand smokers. Confirmation of a significant role of CYP2A13 in the risks of respiratory tract toxicity in humans may lead to new strategies for chemoprevention via enzyme inhibition, and further establish CYP2A13 as an important genetic marker for risk assessment.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
7R01CA092596-13
Application #
9604211
Study Section
Systemic Injury by Environmental Exposure (SIEE)
Program Officer
Johnson, Ronald L
Project Start
2003-04-01
Project End
2021-07-31
Budget Start
2017-11-01
Budget End
2018-07-31
Support Year
13
Fiscal Year
2017
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
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
Fasullo, Michael; Freedland, Julian; St John, Nicholas et al. (2017) An in vitro system for measuring genotoxicity mediated by human CYP3A4 in Saccharomyces cerevisiae. Environ Mol Mutagen 58:217-227
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
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
Liu, Zhihua; Megaraj, Vandana; Li, Lei et al. (2015) Suppression of pulmonary CYP2A13 expression by carcinogen-induced lung tumorigenesis in a CYP2A13-humanized mouse model. Drug Metab Dispos 43:698-702
Spink, Barbara C; Bloom, Michael S; Wu, Susan et al. (2015) Analysis of the AHR gene proximal promoter GGGGC-repeat polymorphism in lung, breast, and colon cancer. Toxicol Appl Pharmacol 282:30-41
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
Li, Lei; Megaraj, Vandana; Wei, Yuan et al. (2014) Identification of cytochrome P450 enzymes critical for lung tumorigenesis by the tobacco-specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK): insights from a novel Cyp2abfgs-null mouse. Carcinogenesis 35:2584-91
Cheng, Wei; Zhang, Rong; Yao, Chun et al. (2014) A critical role of Fas-associated protein with death domain phosphorylation in intracellular reactive oxygen species homeostasis and aging. Antioxid Redox Signal 21:33-45

Showing the most recent 10 out of 53 publications