CYP1A1 GENOTYPE &INDUCIBIL PHENOTYPE-HUM LUNG CA RISK

Project: Research project

Description

DESCRIPTION: Cytochrome P450 lAl
(CYP 1A1), is involved in the bioactivation of a number of
procarcinogenes, including aromatic amines and other hydrocarbons,
important human lung carcinogens. This proposed pilot study focuses
on the relationship between susceptibility to lung cancer risk and (a)
human CYP 1A1 gene polymorphism and (b)CYP 1A1 enzyme inducibility
phenotype, as well as (c) the molecular mechanisms involved in its
induction by polycyclic aromatic hydrocarbons. The working hypothesis is
that the measurements of CYP1A1 enzyme inducibility in HMLs may at
least in part reflect the biological responses in the target lung tissue.
Therefore, higher inducibility in human mononuclear cells (HMLs) may be
a useful biomarker for human lung cancer risk assessment. The primary aim of this study is to compare P-450 lAl enzyme
inducibilities in HMLs and lung alveolar epithelial cells and to
determine their relationships to susceptibility to lung cancer. The
secondary aim is to evaluate the usefulness of CYP 1A1 polymorphism
in lung cancer risk assessment. In addition to the MspI polymorphism,
a new PCR based method to detect polymorphisms not recognized by
restriction enzymes will be also applied. There are at least-two forms
of P-450 1A1 protein present in human lymphocytes dueto point mutation of
the CYP 1A1 gene. This novel point mutation in genotype results in
an amino acid substitution, which might affect enzyme inducibility
phenotype and an individual's risk for oncogenic carcinoma. Finally,
the relationship between enzyme inducibility and CYP 1A1 gene
polymorphism will be also evaluated in order to understand more about
the genetic regulation of CYP 1A1 and its relationship to human lung
carcinogenesis. Lymphocytes and lung epithelial cells will be collected from an ongoing
lung cancer case-control study with a total of 300 subjects (100
lung cancer patients and 200 controls). Inorder to improve the
specificity and sensitivity of the measurement of P-450 lAl enzyme
activities, the applicants have developed a new assay for 1Al, measured by
using HPLC with a fluorescence detector. The assay has sensitivity at
fmol range andis specific for lAl without interference of fluorescenceby
other substances. Results from this pilot study can (1) provide useful
information about the regulation of human CYP1A1 gene expression and
its relationship to an individual's risk of bronchogenic carcinoma,
(2) validate the potential usefulness of these biomarkers in human
leukocytes as a surrogate to predict an individual's risk of bronchogenic
carcinoma, and (3) lead to a more effective chemoprevention design for
bronchogenic carcinoma in a large population-based longitudinal study
planed in the applicant's Institute.
StatusFinished
Effective start/end date9/30/929/29/94

Funding

  • National Institutes of Health: $57,008.00

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Cytochrome P-450 CYP1A1
Genotype
Phenotype
Lung
Lung Neoplasms
Enzymes
Point Mutation
Biomarkers
Lymphocytes
Carcinoma
Alveolar Epithelial Cells
Bronchogenic Carcinoma
Polycyclic Aromatic Hydrocarbons
Chemoprevention
Amino Acid Substitution
Hydrocarbons
Carcinogens
Cytochrome P-450 Enzyme System
Genes
Amines

ASJC

  • Medicine(all)