임신 중 흡연 노출 평가-곽호석

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임신 중 흡연 노출 평가-곽호석

  1. 1. 임신 중 흡연 노출 평가를 위한 바이오 마커 개발 진단검사의학과 곽호석
  2. 2. Tobacco smoke• Tobacco smoke component: > 5,000 chemicals• Electronic database of smoke components: >2,000 chemicals – Mainstream smoke: 542 chemicals • Human inhalation risk: 98 chemicals A list of smoke components needs to be selected with a sufficiently broad chemical, toxicological, and pharmacological profile.
  3. 3. List of harzardous tobacco smoke components Int. J. Environ. Res. Public Health 2011, 8
  4. 4. Int. J. Environ. Res. Public Health 2011, 8
  5. 5. Hazardous tobacco smoke component• The list of Hoffmann analytes: biologically or toxicologically active mainstream smoke components – Based on research from the early 1990s – Only includes carcinogens
  6. 6. The list of Hoffmann analytes Group Analytes Average Yields Group Analytes Average Yields Ammonia (μg/cig) 11.02 1-Aminonaphthalene (ng/cig) 15.1 Hydrogen Cyanide (μg/cig) 109.2 Inorganics Nitric Oxide (μg/cig) 223.41 Aromatic Amines 2-Aminonaphthalene (ng/cig) 10.3 Carbon Monoxide (mg/cig) 11.96 Organics Acrylonitrile (μg/cig) 8.28 3-Aminobiphenyl (ng/cig) 3 1,3-Butadiene (μg/cig) 29.94 4-Aminobiphenyl (ng/cig) 1.7 Benzene (μg/cig) 43.39 Volatile Hydrocarbons Isoprene (μg/cig) 297.68 Methyl ethyl ketone (μg/cig) 62.72 Toluene (μg/cig) 64.91 Acetaldehyde (μg/cig) 560.48 Styrene (μg/cig) 5.11 Acetone (μg/cig) 264.74 Pyridine (μg/cig) 7.02 Nitrogen Heterocyclics Quinoline (μg/cig) 0.23 Carbonyls Acrolein (μg/cig) 58.77 Nicotine (mg/cig) 0.75 (750ug) Butyraldehyde (μg/cig) 29.58 Arsenic (ng/cig) 10.4 Crotonaldehyde (μg/cig) 16.18 Cadmium (ng/cig) 47.8 Formaldehyde (μg/cig) 21.61 Chromium (ng/cig) 73 Propionaldehyde (μg/cig) 43.92 Metals & Metalloids Lead (ng/cig) 33 Catechol (μg/cig) 37.9 Mercury (ng/cig) 3.82 Hydroquinone (μg/cig) 32.4 Nickel (ng/cig) 5.12 m+p-Cresol (μg/cig) 5.84 Selenium (ng/cig) 34.9 Phenols NAB (ng/cig) 16.3 (0.016ug) o-Cresol (μg/cig) 1.89 Tobacco Specific NAT (ng/cig) 119 (0.119ug) Phenol (μg/cig) 7.32 Nitrosamines (TSNAs) NNK (ng/cig) 115.6 (0.116ug) Resorcinol (μg/cig) 0.91 NNN (ng/cig) 133.1 (0.133ug)Polycyclic Aromatic Nicotine-free-dry-particulate-m Benzo[a]pyrene (ng/cig) 7 Tar 8.91Hydrocarbon (PAH) atter (mg/cig)
  7. 7. Biomarkers of tobacco smoke exposure• Carbon monoxide (CO)• Nicotine metabolite: Cotinine• Polycyclic aromatic hydrocarbon (PAHs) metabolite: 2-naphthol, 3- hydroxyfluorenes, 1-hydroxypyrene• Tobacco specific nitrosamines (TSNAs) metabolite: NNAL
  8. 8. Tobacco-specific nitrosamines (TSNAs) Processed tobaccos are invariably contaminated with TSNAs.  Formed during processing (drying and fermentation)  Not present in fresh and green tobaccos Different types of tobacco contain different concentrations of nitrosamines  The higher the nitrate content of tobaccos the higher also the nitrosamine contamination  The high-nitrate tobaccos or other dark tobacco types are high in TSNAs No correlation between the declared tar content of cigarettes and the TSNA concentration in mainstream tobacco smoke No evidence that nicotine is nitrosated during the smoking process
  9. 9. Range for tar, nicotine and tobacco specific nitrosamine (TSNA) in tobacco for commercial cigarettes from several countries
  10. 10. Results of testing for NNK yields from three brands of cigarettes in various countries Nicotine yield range 0.85 mg/cig to 1.3 mg/cig 0.68 mg/cig to 1.25 mg/cigWe see these results as a compelling and urgent argument forgovernment regulation of carcinogen concentrations in cigarettes. Tobacco Control 2000;9:351–354
  11. 11. Chemical structure of TSNAsNitrosation Nitrosamine structure
  12. 12. Formation of tobacco-specific nitrosamines in tobacco
  13. 13. Potential third-hand smoke PNAS ∣ April 13, 2010 ∣ vol. 107 ∣ no. 15
  14. 14. The metabolic activation and inactivation of NNK Steroid hormones Drug: diuretics Drug: block 11β-HSD Drug Drug: flavonoid Flavanone* 11β-HSD: 11β-hydroxysteroid dehydrogenase Similar structure: hormones
  15. 15. Chemical structure of NNAL 11β-HSD
  16. 16. Metabolism of NNK and NNAL and formation of adducts
  17. 17. Structures of characterizedpyridyloxobutyl DNA adducts
  18. 18. Proposed activation pathways for NNN, NNK and NNKOAc
  19. 19. Postulated metabolic pathway mediating the toxicity of NNK Other chemical in smoke
  20. 20. Concentrations of total urinary 4-(methylnitrosamino)- 1-(3-pyridyl)-1-butanol (NNAL) (pg/mg creatinine) and cigarettesper day in 1054 National Health and Nutrition Examination Survey 2007–2008 smokers
  21. 21. Adjusted geometric means in regression model with 95% confidence intervals.
  22. 22. The metabolic activation and inactivation of NNK Steroid hormones Drug: diuretics Drug: block 11β-HSD Drug Drug: flavonoid Flavanone* 11β-HSD: 11β-hydroxysteroid dehydrogenase Similar structure: hormones
  23. 23. Relationships between Cigarette Consumption and Biomarkers of Tobacco Toxin Exposure CO 1-HOP (PAHs metabolite) NNAL Cotinine
  24. 24. Structures of NNK, NNAL, and NNAL-Gluc
  25. 25. Quantitation of Metabolites of NNK after Cessation of Smokeless Tobacco Use Smokeless tobacco Smoking Time post-cessation (days) NNAL t1/2: 10-18 days > cotinine t1/2 : 1days
  26. 26. Metabolizer phenotypes for smokers • PM: poor metabolizer (ratio<2) • IM: intermediate metabolizer (ratio between 2 and 5) • EM: extensive metabolizer (ratio >5)
  27. 27. Comparison of free, conjugated and total urinary NNAL for 60 smokers
  28. 28. NNAL as a Biomarker of exposure to cigarette smoke at the pregnancy• Smoking patterns during pregnancy• Second hand smoke during pregnancy• Fetal exposure
  29. 29. Smoking patterns during pregnancy
  30. 30. Exposure to different sources of second-hand smoke during pregnancy and its effect on urinary cotinine and NNAL concentrations
  31. 31. TOBACCO SMOKING OR EXPOSURE TOSECOND-HAND SMOKE ON THE LEVELS OFNNAL IN URINE OF MOTHER AND NEWBORN
  32. 32. Development of LC-MS/MS for NNAL in urine• Simple sample preparation• Rapid analytical time• High sensitivity
  33. 33. - Sample preparation Enzyme treat Analysis LC- • NNAL-glucuronides MS/MS hydrolysis • Analytical time: • Time: 20h 30min / test Extraction Derivatization • Liquid-Liquid • N-propyl extraction derivatization • Time: 1h • Time: 12h
  34. 34. LC-MS/MS analysis of NNAL Blank UrineLLOQ: 20 pg/mL
  35. 35. LC-MS/MS analysis of NNAL Before enzyme treatment After enzyme treatmentNNAL-glucuronides Concentration:NNAL concentration (After enzyme treatment) – NNAL (Before enzyme treatment)
  36. 36. • Simple sample preparation – Each detection of NNAL and NNAL-glucuronides• Rapid analytical time – Optimization of analytical column• High sensitivity – Optimization of sample preparation
  37. 37. The End

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