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Contribution of drug metabolizing enzymes in gene-gene and gene-environment interactions in lung carcinogenesis

Lerdtragool, Sutira (2002) Contribution of drug metabolizing enzymes in gene-gene and gene-environment interactions in lung carcinogenesis. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Abstract

A panel of metabolic enzyme genetic polymorphisms, which are involved in cigarette carcinogen metabolism, also a DNA repair gene involved in the nucleotide excision repair pathway were evaluated for associations with lung cancer risk in 203 lung cancer cases and 205 controls and in a case-only analysis of 177 lung cancer patients. Significant relationships between predicted high CYP1A2 activity, CYP1B1 (*1/*3 or *3/*3), GSTM3*A/*A, and XPD (Lys/Gln or Gln/Gln) genotypes and lung cancer risk were observed (adjusted ORs, 2.05; 95%CI, 1.13-3.73, 2.6; 95%CI, 1.19-5.69, 1.84; 95%CI, 1.03-3.31, 2.56; 95%CI, 1.45-4.51, respectively). The predicted mEPHX intermediate or high activity genotype also increased risk approximately 3-fold among females. The combined effects of carrying multiple genetic polymorphisms (gene-gene interaction) or of gene-environment interactions, for example, between the CYP1B1 (*1/*3 or *3/*3) genotype and packyear also resulted in significant levels of increased risk and early age onset of lung cancer. CYP mRNA expression levels were measured in 20 pairs of lung tumor and histologically normal tissues to evaluate the potential for local metabolic activation and as a smoking exposure biomarker. The detection of CYP1B1 and CYP2E1 mRNA expression in lung tissue suggests that local bioactivation of procarcinogens may occur. A relationship between lung CYP2E1 mRNA expression levels and cigarette smoke and/or other environmental carcinogens exposure was observed. The significant increase in the levels of CYP2E1 mRNA expression in lung tumors compared to their corresponding histological normal adjacent tissues among current and former smokers and nonsmokers who were exposed to petroleum and/or other environmental exposures further suggest a mechanistic link between environmental carcinogens exposures and lung cancer development. The results indicate that individual susceptibility to lung cancer determined by endogenous host factors such as genetic polymorphisms in metabolic and DNA repair genes, family history of lung and other cancers, early age onset, and interindividual differences in capacity of local procarcinogens bioactivation could interact with each other and/or interact with individual exposures or other exogenous factors such as cigarette smoke, environmental carcinogens and occupational exposures in modifying lung cancer risk.


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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Lerdtragool, Sutirasulst5@pitt.eduSULST5
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairRomkes, Marjorieromkes@msx.dept-med.pitt.eduROMKES
Committee MemberDay, Billy Wbday@pitt.eduBDAY
Committee MemberSiegfried, Jill Msiegfrie@server.pharm.pitt.edu
Committee MemberWilson, John Wjww@pitt.eduJWW
Committee MemberKeohavong, Phouthonepho1@pitt.eduPHO1
Date: 27 November 2002
Date Type: Completion
Defense Date: 16 September 2002
Approval Date: 27 November 2002
Submission Date: 26 September 2002
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Institution: University of Pittsburgh
Schools and Programs: Graduate School of Public Health > Environmental and Occupational Health
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: DNA repair; gene expression; genetic susceptibility; lung cancer risk assessment; TaqMan assay
Other ID: http://etd.library.pitt.edu:80/ETD/available/etd-09262002-124546/, etd-09262002-124546
Date Deposited: 10 Nov 2011 20:02
Last Modified: 19 Dec 2016 14:37
URI: http://d-scholarship.pitt.edu/id/eprint/9390

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