Advertisement

Genetische Suszeptibilität im Hinblick auf toxische Arbeitsplatz- und Umweltbelastungen

  • Ricarda Thier
  • K. Golka
  • Th. Brüning
  • H. M. Bolt
Chapter

Zusammenfassung

Eine wichtige Ursache individuell unterschiedlicher Ansprechbarkeiten gegenüber Fremdstoffen liegt in der Variabilität der Gene, die für fremdstoffmetabolisierende Enzyme kodieren. Für die Arbeits- und Umweltmedizin sind vor allem Polymorphismen verschiedener Isoformen des Cytochrom P450, der N-Acetyl-Transferase (NAT2) und der Glutathiontransferase (GSTT1, GSTM1) wichtig geworden. Aus arbeitsmedizinischer Sicht erscheint das Cytochrom P450 Isoenzym CYP2E1 als Schlüsselenzym des oxydativen Stoffwechsels vieler bedeutsamer Grundchemikalien der chemischen Industrie; es oxydiert eine Reihe von Alkenen, Aromaten und halogenierten Kohlenwasserstoffen. Die Isoenzyme der Glutathiontransferase GSTT1 und GSTM1 sind wichtig im Metabolismus von organischen Lösemitteln, Kunststoffmonomeren und Intermediaten polyzyklischer aromatischer Kohlenwasserstoffe. Der Einfluß der N-Acetyltransferase 2 (NAT2) bei der Auslösung von Urothelkarzinomen bei Exposition gegen aromatische Amine hat als erwiesen zu gelten; die N-Oxidation aromatischer Amine, die zu deren „Giftung“ führt, wird bei „langsamen“ Acetylierern vermehrt beschritten. Es ist insgesamt evident, daß Polymorphismen fremdstoffmetabolisierender Enzyme die Wirkungen toxischer Stoffe entscheidend modulieren. Bei weiter zu erwartendem Fortschritt der Erkenntnisse auf diesem Gebiet werden sich hieraus ergebende präventivmedizinische und soziopolitische Aspekte verstärkt zu diskutieren sein.

Schlüsselwörter

Fremdstoffmetabolismus Polymorphismus Cytochrom P450 Glutathiontransferase (GST) N-Acetyltransferase (NAT2) 

Genetic susceptibility to toxicants at the workplace and in the environment

Summary

The variability of genes coding for xenobiotic metabolizing enzymes is an important reason for individual variations in susceptibilities towards chemical toxicants. In environmental and occupational medicine, polymorphisms of different isoforms of cytochrome P450, of N-acetyl-transferase (NAT2) and of glutathione transferase (GSTT1, GSTM1) are now of importance. In particular, the cytochrome P450 isoenzyme CYP2E1 is a key enzyme of the oxidative metabolism of highly relevant industrial chemicals as it metabolizes alkenes as well as aromatic and halogenated hydrocarbons. The influence of N-acetyltransferase 2 (NAT2) on the carcinogenic effect of aromatic amines upon the urothelium has been well established;the N-oxidation of aromatic amines leading to toxic and carcinogenic intermediates is higher in „slow“ compared to „rapid“ acetylators. In general, it is now evident that polymorphisms of xenobiotic metabolizing enzymes may have a decisive role in modulating the effects of toxicants on humans. Further progress in this field is to be expected, and calls for intensive discussion of both the preventiv and sociopolitical aspects.

Key words

Xenobiotic Metabolism Polymorphism Cytochrome P450 Glutathione Transferase (GST) N-acetyltransferase (NAT2) 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

Literatur

  1. 1.
    Zbinden G (1992) The three eras of research in experimental toxicology. TIPS 13: 221–223.PubMedGoogle Scholar
  2. 2.
    Bolt HM (1994) Genetic and individual differences in the process of biotransformation and their relevance for occupational medicine. Med Lav 85:37–48.PubMedGoogle Scholar
  3. 3.
    Vainio H (1999) Biomarkers in the identification of risks, especially with regard to susceptible persons and subgroups. Scand J Work Environ Health 25:1–3.PubMedCrossRefGoogle Scholar
  4. 4.
    Idle JR, Armstrong M, Boddy A et al. (1992) The pharmacogenetics of chemical carcinogenesis. Pharmacogenetics 2:246–258.PubMedCrossRefGoogle Scholar
  5. 5.
    Kouri RE, McKinney CE, Slomiang DJ et al. (1982) Positive correlation between high aryl hydrocarbon hydroxylase activity and primary lung cancer as analyzed in cytopreserved lymphocytes. Cancer Res 42:5030–5037.PubMedGoogle Scholar
  6. 6.
    Butler MA, Lang NP, Young JF et al. (1992) Determination of CYP1A2 and N-acetyltransferase 2 phenotypes in human population b, analysis of caffeine urinary metabolites. Pharmacogenetics 2:116–127.PubMedCrossRefGoogle Scholar
  7. 7.
    Crespi CL, Penman BW, Gelboin HV, Gonzales FJ (1991) A tobacco-smoke derived nitrosamine, 4-(methylnitrosamino)-1-(3-pyridyl)-1 — butanone, is activated by multiple human P-450 s including the polymorphic P-450 2D6. Carcinogenesis 12:1197–1201.PubMedCrossRefGoogle Scholar
  8. 8.
    Lin L, Yang F, Ye E et al. (1991) Case-control study of cigarette smoking and primary hepatoma in an aflatoxin-endemic region in China: a protective effect. Pharmacogenetics 1:79–85.PubMedCrossRefGoogle Scholar
  9. 9.
    Carrière V, Berthou F, Baird S, Belloc C, Beaune P, de Waziers J (1996) Human cytochrome P4502E1 (CYP2E1): from genotype to phenotype. Pharmacogenetics 6:203–211.PubMedCrossRefGoogle Scholar
  10. 10.
    Kempkes M, Wiebel FA, Golka K, Heitmann P, Bolt HM (1996) Comparative genotyping and phenotyping of glutathione S-transferase GSTT1. Arch Toxicol 70:306–309.PubMedCrossRefGoogle Scholar
  11. 11.
    Shen JH, Lin GF, Yuan WX, Tan JW, Bolt HM, Thier R (1998) Glutathione transferase T1 and M1 genotype polymorphism in the normal population of Shanghai. Arch Toxicol 72:456–458.PubMedCrossRefGoogle Scholar
  12. 12.
    Hallier E (1996) Arbeitsmedizinische Untersuchungen zur Problematik der Durchführung von Begasungen mit Methylbromid. Deutsche Hochschulschriften, Nr. 1089. Hänsel-Hohenhausen, Egelsbach.Google Scholar
  13. 13.
    Garnier R, Rambourg-Schepens MO, Müller A, Hallier E (1996) Glutathione transferase activity and formation of macromolecular adducts in two cases of acute methyl bromide poisoning. Occup Environ Med 53:211–215.PubMedCrossRefGoogle Scholar
  14. 14.
    Bus JS (1982) Integrated studies of methyl chloride toxidty. CUT Activities 2(1): 3–5.Google Scholar
  15. 15.
    Vollmer DM, Thier R, Bolt HM (1998) Determination of the ethylene oxide adduct S-(2-hydroxyethyl)cysteine by a fluorometric HPLC method in albumin and globin from human blood. Fresenius J Anal Chem 362:324–328.CrossRefGoogle Scholar
  16. 16.
    Thier R, Lewalter J, Kempkes M, Selinski S, ßrüning T, Bolt HM (1999) Haemoglobin adducts of acrylonitrile and ethylene oxide in acrylonitrile workers, dependent on polymorphismus of the glutathione transferases GSTT1 and GSTM1. Arch Toxicol 73: (im Druck).Google Scholar
  17. 17.
    Risch A, Wallace DMA, Bathers S, Sim E (1995) Slow acetylation genotype is a susceptibility factor in occupational and smoking related bladder cancer. Hum Mol Genet 4:231–236.PubMedCrossRefGoogle Scholar
  18. 18.
    Golka K, Prior V, Blaszkewicz M, Cascorbi I, Schöps W, Kierfeld G, Roots I, Bolt HM (1996) Occupational history and genetic N-acetyltransferase polymorphism in urothelial cancer patients of Leverkusen, Germany. Scand J Work Environ Health 22:332–338.PubMedCrossRefGoogle Scholar
  19. 19.
    Schöps W, Prior V, Golka K, Blaszkewicz M, Cascorbi I, Roots I, Bolt HM, Kierfeld G (1997) Untersuchungen zur klinischen Relevanz der Acetyliererphänotypisierung bei 196 Urotheltumor-Patienten. Urologe[A] 36:64–67.CrossRefGoogle Scholar
  20. 20.
    Lewalter J, Miksche LW (1991) Empfehlungen zur arbeitsmedizinischen Prävention expositions-und dispositionsbedingter Arbeitsstoff-Beanspruchungen. Verh Dtsch GesArbeitsmed 31:135–139.Google Scholar
  21. 21.
    Golka K, Reckwitz T, Kempkes M, Cascorbi I, Blaszkewicz M, Reich SE, Roots I, Soekeland J, Schulze H, Bolt HM (1997) N-Acetyltransferase 2 (NAT2) and glutathione S-transferase (GSTM1) in bladder-cancer patients in a highly industrialized area. Int J Occup Environ Health 3:105–110.PubMedGoogle Scholar
  22. 22.
    Brüning T, Chronz C, Thier R, Havelka J, Ko Y, Bolt HM (1999) Occurrence of urinary tract tumours in miners highly exposed to dinitrotoluene. J Occup Environ Med 41:144–149.PubMedCrossRefGoogle Scholar
  23. 23.
    Myslak ZW, Bolt HM, Brockmann W (1991) Tumors of the urinary bladder in painters: a case-control-study. Am J Ind Med 19:705–713.PubMedCrossRefGoogle Scholar
  24. 24.
    Bolt HM (1995) Special points in the toxicity assessment of colorants (dyes and pigments) In: Thomas H, Hess R, Waechter F (eds) Toxicology of Industrial Compounds.Taylor & Francis, London, pp 303–310.Google Scholar
  25. 25.
    Golka K, Kempkes M, Flieger A, Blaszkewicz M, Bolt HM (1997) Overrepresentation of the slow acetylator phenotype in painters suffering from urinary bladder cancer. Med Lav 88:425–426.PubMedGoogle Scholar
  26. 26.
    Von Schmiedeberg S, Fritsche E, Rönnau AC, Golka K, Specker C, Schuppe HC, Döhr O, Sachs B, Bolt HM, Lehmann P, Ruzicka T, Esser C, Abel J, Gleichmann E (1996) Polymorphisms of drug-metabolizing enzymes in patients with iseopathic systemic autoimmune diseases. Exp Toxic Pathol 48 [Suppl] 2:349–353.Google Scholar
  27. 27.
    Rocha R, Garcia C, de Mendonca A, Gil JP, Bishop DT, Lechner MC (1999) N-acetyltransferase (NAT2) genotype and susceptibility to sporadic Alzheimer’s disease. Pharmacogenetics 9:9–15.PubMedCrossRefGoogle Scholar
  28. 28.
    Atkinson A, Singleton AB, Steward A, Ince PG, Perry RH, McKeith IG, Fairbairn AF, Edwardson JA, Daly AK, Morris CM (1999) CYP2D6 is associated with Parkinson’s disease but not with dementia with Lewy Bodies or Alzheimer’s disease. Pharmacogenetics 9:31–35.PubMedCrossRefGoogle Scholar
  29. 29.
    Kempkes M, Golka K, Reich S, Reckwitz T, Bolt HM (1996) Comparative genotyping and phenotyping of glutathione S-transferase GSTM1 and GSTT1 null genotypes as potential risk factors for urothelial cancer of the bladder. Arch Toxicol 71:123–126.PubMedCrossRefGoogle Scholar
  30. 30.
    Warholm M, Alexandrie AK, Hogberg J, Sigvardsson K, Rannug A (1994) Polymorphic distribution of glutathione transferase activity with methyl chloride in human blood. Pharmacogenetics 4:307–311.PubMedCrossRefGoogle Scholar
  31. 31.
    Chen CL, Liu Q, Relling MV (1996) Simultaneous characterization of glutathione S-transferase M1 and T1 polymorphisms by polymerase chain reaction in American whites and blacks. Pharmacogenetics 2:187–191.CrossRefGoogle Scholar
  32. 32.
    Lee EJ, Wong JY, Yeoh PN, Gong NH (1995) Glutathione S-transferase-theta (GSTT1) genetic polymorphism among Chinese, Malays and Indians in Singapore. Pharmacogenetics 5:332–334.PubMedCrossRefGoogle Scholar
  33. 33.
    Katoh T, Nagata, N, Kuroda Y, Itoh H, Kawahara A, Kuroki N, Ookuma R, Bell DA (1996) Glutathione S-transferase M1 (GSTM1) and T1 (GSTT1) genetic polymorphism and susceptibility to gastric and colorectal adenocarcionoma. Carcinogenesis 17:1855–1859.PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 1999

Authors and Affiliations

  • Ricarda Thier
    • 1
  • K. Golka
    • 1
  • Th. Brüning
    • 1
  • H. M. Bolt
    • 1
  1. 1.Institut für ArbeitsphysiologieUniversität DortmundDortmundDeutschland

Personalised recommendations