Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2005, 149(2):191-197 | DOI: 10.5507/bp.2005.025

MOLECULAR MECHANISM OF GENOTOXICITY OF THE ENVIRONMENTAL POLLUTANT 3-NITROBENZANTHRONE

Marie Stiborováa, Volker M. Arltb, Colin J. Hendersonc, C. Roland Wolfc, Eva Freid, Heinz H. Schmeiserd, David H. Phillipsb
a Department of Biochemistry, Faculty of Science, Charles University, Albertov 2030, 12840 Prague 2, Czech Republic
b Section of Molecular Carcinogenesis, Institute of Cancer Research, Brookes Lawley Building, Sutton, Surrey SM2 5NG, United Kingdom
c Cancer Research UK Molecular Pharmacology Unit, Biomedical Research Centre, Dundee DD1 9SY, United Kingdom
d Division of Molecular Toxicology, German Cancer Research Center, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany

3-Nitrobenzanthrone (3-NBA) is a suspected human carcinogen identified in diesel exhaust and air pollution. This article reviews the results of our laboratories showing which of the phase I and II enzymes are responsible for 3-NBA genotoxicity, participating in activation of 3-NBA and its human metabolite, 3-aminobenzanthrone (3-ABA), to species generating DNA adducts. Among the phase I enzymes, the most of the activation of 3-NBA in vitro is attributable to cytosolic NAD(P)H:quinone oxidoreductase (NQO1), while N,O-acetyltransferase (NAT), NAT2, followed by NAT1, sulfotransferase (SULT), SULT1A1 and, to a lesser extent, SULT1A2 are the major phase II enzymes activating 3- NBA. To evaluate the importance of hepatic cytosolic enzymes in relation to microsomal NADPH:cytochrome P450 (CYP) oxidoreductase (POR) in the activation of 3-NBA in vivo, we treated hepatic POR-null and wild-type C57BL/6 mice with 3-NBA or 3-ABA. The results indicate that 3-NBA is predominantly activated by cytosolic nitroreductases such as NQO1 rather than microsomal POR. In the case of 3-ABA, CYP1A1/2 enzymes are essential for the oxidative activation of 3-ABA in liver. However, cells in the extrahepatic organs have the metabolic capacity to activate 3-ABA to form DNA adducts, independently from CYP-mediated oxidation in the liver. Peroxidases such as prostaglandin H synthase, lactoperoxidase, myeloperoxidase, abundant in several extrahepatic tissues, generate DNA adducts, which are formed in vivo by 3-ABA or 3-NBA. The results suggest that both CYPs and peroxidases may play an important role in metabolism of 3-ABA to reactive species forming DNA adducts, participating in genotoxicity of this compound and its parental counterpart, 3-NBA.

Keywords: 3-Nitrobenzanthrone, 3-Aminobenzanthrone, Cytochrome P450, NAD(P)H:quinone oxidoreductase, Peroxidase,

Received: June 10, 2005; Accepted: September 25, 2005; Published: December 1, 2005  Show citation

ACS AIP APA ASA Harvard Chicago IEEE ISO690 MLA NLM Turabian Vancouver
Stiborová, M., Arlt, V.M., Henderson, C.J., Roland Wolf, C., Frei, E., Schmeiser, H.H., & Phillips, D.H. (2005). MOLECULAR MECHANISM OF GENOTOXICITY OF THE ENVIRONMENTAL POLLUTANT 3-NITROBENZANTHRONE. Biomedical papers149(2), 191-197. doi: 10.5507/bp.2005.025
Download citation

References

  1. Boffetta P, Nyberg F. (2003) Contribution of environmental factors to cancer risk. Br Med Bull 68, 71-94. Go to original source... Go to PubMed...
  2. Vineis P, Forastiere F, Hoek G, Lipsett M. (2004) Outdoor air pollution and lung cancer: recent epidemiologic evidence. Int J Cancer 111, 647-52. Go to original source... Go to PubMed...
  3. Enya T, Suzuki H, Watanabe T, Hirayama T, Hisamatsu Y. (1997) 3-Nitrobenzanthrone, a powerful bacterial mutagen and suspected human carcinogen found in diesel exhausts and airborne particulates. Environ Sci Technol 31, 2772-6. Go to original source...
  4. Seidel A, Dahmann D, Krekeler H, Jacob J. (2002) Biomonitoring of polycyclic aromatic compounds in the urine of mining workers occupationally exposed to diesel exhaust. Int J Hyg Environ Health 204, 333-8. Go to original source... Go to PubMed...
  5. Arlt VM, Zhan L, Schmeiser HH, Honma M, Hayashi M, Phillips DH, Suzuki T. (2004) DNA adducts and mutagenic specificity of the ubiquitous environmental pollutant 3-nitrobenzanthrone in Muta Mouse. Environ Mol Mutagen 43, 186-95. Go to original source... Go to PubMed...
  6. Arlt VM, Bieler CA, Mier W, Wiessler M, Schmeiser HH. (2001) DNA adduct formation by the ubiquitous environmental contaminant 3-nitrobenzanthrone in rats determined by 32P-postlabeling. Int J Cancer 93, 450-4. Go to original source... Go to PubMed...
  7. Arlt VM, Sorg BL, Osborne M, Hewer A, Seidel A, Schmeiser HH, Phillips DH. (2003) DNA adduct formation by the ubiquitous environmental pollutant 3-nitrobenzanthrone and its metabolites in rats. Biochem Biophys Res Commun 300, 107-14. Go to original source... Go to PubMed...
  8. Arlt VM, Glatt H, Muckel E, Pabel U, Sorg BL, Schmeiser HH, Phillips DH. (2002) Metabolic activation of the environmental contaminant 3-nitrobenzanthrone by human acetyltransferases and sulfotransferase. Carcinogenesis 23, 1937-45. Go to original source... Go to PubMed...
  9. Arlt VM, Stiborova M, Hewer A, Schmeiser HH, Phillips DH. (2003) Human enzymes involved in the metabolic activation of the environmental contaminant 3-nitrobenzanthrone: evidence for reductive activation by human NADPH:cytochrome P450 reductase. Cancer Res 63, 2752-61.
  10. Nagy E, Zeisig M, Kawamura K, Hisamatsu Y, Sugetta A, Adachi S. Moller L (2005) DNA-adduct and tumor formations in rats after intratracheal administration of the urban air pollutant 3-nitrobenzanthrone. Carcinogenesis 26, 1821-1828. Go to original source... Go to PubMed...
  11. Arlt VM, Stiborova M, Henderson CJ, Osborne MR, Bieler CA, Frei E, Martinek V, Sopko B, Wolf CR, Schmeiser HH, Phillips DH. (2005) The environmental pollutant and potent mutagen 3-nitrobenzanthrone forms DNA adducts after reduction by NAD(P)H: quinone oxidoreductase and conjugation by acetyltransferases and sulfotransferases in human hepatic cytosols. Cancer Res 65, 2644- 52. Go to original source... Go to PubMed...
  12. Ross D, Kepa JK, Winski SL, Beall HD, Anwar A, Siegel D. (2000) NAD(P)H:quinone oxidoreductase (NQO1): chemoprotection, bioactivation, gene regulation and genetic polymorphisms. Chem Biol Interact 129, 77-97. Go to original source... Go to PubMed...
  13. Arlt VM, Glatt H, Muckel E, Pabel U, Sorg BL, Seidel A, Frank H, Schmeiser HH, Phillips DH. (2003) Activation of 3-nitrobenzanthrone and its metabolites by human acetyltransferases, sulfotransferases and cytochrome P450 expressed in Chinese hamster V79 cells. Int J Cancer 105, 583-92. Go to original source... Go to PubMed...
  14. Hein DW, Doll MA, Fretland AJ, Leff MA, Webb SJ, Xiao GH, Devanaboyina US, Nangju NA, Feng Y. (2000) Molecular genetics and epidemiology of the NAT1 and NAT2 acetylation polymorphisms. Cancer Epidemiol Biomarkers Prev 9, 29-42.
  15. Glatt H, Boeing H, Engelke CEH, Ma L, Kuhlow A, Pabel U, Pomplun D, Teubner W, Meinl W. (2001) Human cytosolic sulphotransferases: genetics, characteristics, toxicological aspects. Mutat Res 482, 27-40. Go to original source... Go to PubMed...
  16. Schulz WA, Krummeck A, Rosinger I, Eickelman C, Neuhas C, Ebert T, Schmitz-Drager B, Sies H. (1997) Increased frequency of a null allele for NAD(P)H:quinone oxidoreductase in patients with urological malignancies. Pharmacogenetics 7, 235-9. Go to original source... Go to PubMed...
  17. Wiemels J, Pagnamenta A, Taylor GM, Eden OB, Alexander FE, Greaves MF. (1999) A lack of functional NAD(P)H:quinone oxidoreductase allele is selectively associated with pediatric leukemias that have MLL fusions. United Kingdom Childhood Cancer Study Investigators. Cancer Res 59, 4095-9.
  18. Wu MT, Wang YT, Ho CK, Wu DC, Lee YC, Hsu HK, Kao EL, Lee JM. (2003) SULT1A1 polymorphism and esophageal cancer in males. Int J Cancer 103, 101-4. Go to original source... Go to PubMed...
  19. Henderson CJ, Otto DME, Carrie D, Magnuson MA, McLaren AW, Rosewell I, Wolf CR. (2003) Inactivation of the hepatic cytochrome P450 system by conditional deletion of hepatic cytochrome P450 reductase. J Biol Chem 278, 13480-6. Go to original source... Go to PubMed...
  20. Arlt VM, Hewer A, Sorg BL, Schmeiser HH, Phillips DH, Stiborova M. (2004) 3-Aminobenzanthrone, a human metabolite of the environmental pollutant 3-nitrobenzanthrone, forms DNA adducts after metabolic activation by human and rat liver microsomes: evidence for activation by cytochrome P450 1A1 and P450 1A2. Chem Res Toxicol 17, 1092-101. Go to original source... Go to PubMed...
  21. Arlt VM, Henderson CJ, Wolf CR, Schmeiser HH, Phillips DH, Stiborová M. (2005) Bioactivation of 3-aminobenzanthrone, a human metabolite of the environmental pollutant 3-nitrobenzanthrone: evidence for DNA adduct formation mediated by cytochrome P450 enzymes and peroxidases. Cancer Lett., Epub ahead of print 7. May 2005. Go to original source...
  22. Wiese FW, Thompson PA, Kadlubar FF. (2001) Carcinogen substrate specificity of human COX-1 and COX-2. Carcinogenesis 21, 5-10. Go to original source... Go to PubMed...
  23. Williams JA. (2001) Single nucleotide polymorphisms, metabolic activation and environmental carcinogenesis: why molecular epidemiologists should think about enzyme expression. Carcinogenesis 22, 209-14. Go to original source... Go to PubMed...
  24. Borlak J, Hansen T, Yuan Z, Sikka HC, Kumar S, Schmidbauer S, Frank H, Jacob J, Seidel A. (2000) Metabolism and DNA-binding of 3-nitrobenzanthrone in primary rat alveolar type II cells, in human fetal bronchial, rat epithelial and mesenchymal cell lines. Polycyclic Aromat. Compounds 21, 73-86. Go to original source...
  25. Williams JA, Phillips DH. (2000) Mammary expression of xenobiotic metabolizong enzymes and their potential role in breast cancer. Cancer Res 60, 4667-77. Go to PubMed...
  26. Williams JA, Stone EM, Millar BC, Hewer A, Phillips DH. (2000) Pathways of heterocyclic amine activation in the breast: DNA adducts of 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) formed by peroxidases and in human mammary epithelial cells and fibroblasts. Mutagenesis 15, 49-154. Go to original source... Go to PubMed...
  27. Gorlewska-Roberts KM, Teitel CH, Lay JO Jr., Roberts DW, Kadlubar FF. (2004) Lactoperoxidase-catalyzed activation of carcinogenic aromatic and heterocyclic amines. Chem Res Toxicol 17, 1659-66. Go to original source... Go to PubMed...