MOLECULAR MECHANISMS INFLUENCING THE BIOMARKER LEVELS OF ENVIRONMENTAL GENOTOXIC EXPOSURE

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MOLECULAR MECHANISMS INFLUENCINGTHE BIOMARKER
LEVELS OF ENVIRONMENTALGENOTOXIC EXPOSURE

• Bernadette Schoket

Department of Molecular Environmental
Epidemiology National Institute of Environmental
Health József Fodor National Centre for Public
Health Budapest, Hungary
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IMPORTANT ISSUES IN HUMAN BIOMONITORING

• ? The use of surrogate and target tissues to
  estimate environmental genotoxic exposure
• ? The modulation of biomarker levels by genetic
  susceptibility factors

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AIMS OF THE STUDY

• Correlation between smoking-related bulky
  carcinogen-DNA adduct levels in lung tissues
• and in peripheral blood lymphocytes
• The influence of glutathione S-transferase
  metabolic genotypes on the DNA adduct levels
  induced by cigarette smoking

?
?
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STUDY POPULATION
Lung cancer patients undergoing lung
resection, N 212
Normal bronchus Normal peripheral lung Peripheral
blood lymphocytes
SMOKING STATUS
Current Smokers Life-time Non-smokers
Short-term Ex-smokers Long-term
Ex-smokers ( ? 1 year of abstinence )
( gt 1 year of abstinence )
SMOKERS NON-SMOKERS
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? DETERMINATION OF BULKY CARCINOGEN-DNA ADDUCTS
METHODOLOGY
32P-Postlabelling
? DETERMINATION OF GENOTYPES
PCR and PCR-RFLP
GSTM1 GSTT1 GSTP1 Ile105Val
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BULKY DNA ADDUCTS IN TISSUES FROM CURRENT SMOKER
LUNG CANCER PATIENTS
Lung tumour Normal lung Normal
bronchus Blood lymphocytes
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LEVELS OF BULKY DNA ADDUCTS IN LUNG TISSUES AND
PERIPHERAL BLOOD LYMPHOCYTES
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CORRELATION BETWEEN BULKY DNA ADDUCT LEVELS IN
NORMAL PERIPHERAL LUNG AND BRONCHIAL TISSUES

• Smokers r0.83 Plt0.0001 (N38)
• Non-smokers r0.73 Plt0.0001 (N30)

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CORRELATION BETWEEN DNA ADDUCT LEVELS IN LUNG
TISSUES AND LYMPHOCYTES
FOR SMOKERS AND NON-SMOKERS
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GSTM1 AND GSTT1 GENOTYPES AND BULKY DNA ADDUCT
LEVELS IN BRONCHUS
GSTM1
GSTM1GSTT1
GSTT1
Smokers
Non-smokers
Smokers
Non-smokers
Smokers
Non-smokers
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THE EFFECT OF GSTP1 Ile105Val GENOTYPE ON BULKY
DNA ADDUCT LEVELS IN BRONCHUS
Smokers
Non-smokers
P0.012


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MAIN CONCLUSIONS

• ? The dose of exposure and the metabolic
  capacity of
• the tissues influence the correlation between
  target
• and surrogate tissue
• ? Genetic polymorphisms of xenobiotic-metabolisin
  g enzymes may affect the biologically effective
  dose of genotoxic exposure
• ? Implications for human biomonitoring
• ? low dose - high dose exposure
• ? surrogate - target tissue
• ? metabolic genotypes - biomarker levels

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PARTICIPANTS OF THE STUDY
National Institute of Environmental Health,
Budapest, Hungary Bernadette Schoket Erika
Gyorffy Lívia Anna National Center for
Epidemiology, Budapest, Hungary Judit
Segesdi János Minárovits Zoltán Gyori National
Institute of Pulmonology, Budapest,
Hungary Ibolya Soltész Szilárd Kostic Attila
Csekeo