Date of Award

1-1-2009

Language

English

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

College/School/Department

Department of Environmental Health Sciences

Content Description

1 online resource (xii, 146 pages) : illustrations (some color)

Dissertation/Thesis Chair

Xinxin Ding

Committee Members

Lawrence S. Kaminsky, David C. Spink, Michelle Caggana, Robert J. Turesky

Keywords

CYP2A13, gene regulation, pharmacogenetics, single nucleotide polymorphism, Cytochrome P-450, Gene expression, Genetic regulation, Individual differences, Lungs

Subject Categories

Toxicology

Abstract

The overall goal of this dissertation is to investigate the mechanisms underlying the large interindividual variations in susceptibility to lung carcinogenesis. We focused on CYP2A13, a respiratory tract-specifically expressed enzyme, which is the most efficient P450 towards bioactivation of a tobacco-related carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). The expression level of CYP2A13 varies substantially among human lung samples. Our central hypothesis is that CYP2A13 expression level is affected by both genetic regulators and non-genetic factors. The specific aims are 1) to identify the mechanisms underlying the decreased allelic expression of a CYP2A13 allele (7520C>G); 2) to identify frequent single-nucleotide polymorphisms (SNPs), associated with altered allelic expression, in the CYP2A13 gene and flanking intergenic regions; 3) to examine the effects of inflammation on CYP2A13 expression and dissect the underlying mechanisms.

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