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Protection by indomethacin and aspirin against genotoxicity of ochratoxin A, particularly in the urinary bladder and kidney

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Abstract

Ochratoxin A (OTA) is a ubiquitous nephrotoxic mycotoxin which was shown to be carcinogenic to laboratory animals and may be responsible for kidney pelvis, ureter and urinary bladder tumors associated with Balkan endemic nephropathy in man. Previous evidence from this laboratory demonstrated that OTA exposure results in adduct formation on kidney, testicles, liver and spleen DNA. We show in this study that after a single oral administration of OTA to mice (2 mg/kg body weight) a high level of DNA adducts (150 per 109 nucleotides) is also detected in the urinary bladder. The metabolic pathway of OTA leading to genotoxic compounds is not yet known. We demonstrate here that two inhibitors of the prostaglandin H synthase, indomethacin and aspirin, administered to mice before OTA treatment, dramatically reduce the amounts of DNA adducts, particularly in the urinary bladder and kidney. This suggests a role of protaglandin H synthase in the metabolism of OTA leading to active metabolites which react with DNA.

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References

  1. Battista JR, Marnett LJ (1985) Prostaglandin H synthase-dependant oxidation of aflatoxin B1. Carcinogenesis 6: 1227–1229

    Article  PubMed  CAS  Google Scholar 

  2. Bendele AM, Carlton WW, Krogh P, Lillehoj EB (1985) Ochratoxin A carcinogenesis in the (C57BL/6JxC3H)F1 mouse. J Natl Cancer Inst 75: 733–742

    PubMed  CAS  Google Scholar 

  3. Castegnaro M, Chernozemsky IN, Hietanen E, Bartsch H (1990) Are mycotoxins risk factors for endemic nephropathy and associated urothelial cancers? Arch Geschwulstforsch 60: 295–303

    PubMed  CAS  Google Scholar 

  4. Ceovic S, Plestina R, Miletic-Medved M, Stavljenic A, Mitar J, Vukelic M (1991) Epidemiological aspects of Balkan endemic nephropathy in a typical focus in Yugoslavia. In: Castegnaro M, Plestina R, Dirheimer G, Chernozemsky IN, Bartsch H (eds) Mycotoxin, endemic nephropathy and urinary tract tumours. IARC Scientific Publications vol. 115, International Agency for Research on Cancer, Lyon, pp 5–10

    Google Scholar 

  5. Christ EJ, Van Dorp DA (1972) Comparative aspects of prostaglandin biosynthesis in animal tissue. Biochim Biophys Acta 270: 537–545

    CAS  Google Scholar 

  6. Creppy EE, Betbeder AM, Gharbi A, Gauret MF, Andrieux M, Counord J, Bartsch H, Castegnaro M, Fouillet B, Chambon P, Grosse Y, Pfohl-Leszkowicz A, Dirheimer G, Mériaux J, Guiot-Guillain M, Douet C, Manier C, Giacomotto P, Vezon G, Montcharmont P, Waller JP, Laustriat D, Cazenave JP (1993) Etude de l’ochratoxicose humaine dans trois régions de France: Alsace, Aquitaine et région Rhône-Alpes. In: Creppy EE, Castegnaro M, Dirheimer G (eds) Human ochratoxicosis and its pathologies. Les Editions INSERM. vol. 231. John Libbey Eurotext, Montrouge, pp 147–158

    Google Scholar 

  7. Degen GH (1990) Role of protaglandin-H synthase in mediating genotoxic and carcinogenic effects of estrogens. Environ Health Perspect 88: 217–223

    Article  PubMed  CAS  Google Scholar 

  8. Delacruz L, Bach PH (1990) The role of ochratoxin A metabolism and biochemistry in animal and human nephrotoxicity. J Biopharmaceut Sci 1: 277–304

    CAS  Google Scholar 

  9. Dirheimer G, Creppy EE (1991) Mechanism of action of ochratoxin A. In: Castegnaro M, Plestina R, Dirheimer G, Chernozemsky IN, Bartsch H (eds) Mycotoxin, endemic nephropathy and urinary tract tumours. IARC Scientific Publications, vol. 115, International Agency for Research on Cancer, Lyon, pp 171–186

    Google Scholar 

  10. Eling T, Boyd J, Reed G, Mason R, Sivarajah K (1983) Xenobiotic metabolism by prostaglandin endoperoxide synthetase. Drug Metab Rev 14: 1023–1053

    Article  PubMed  CAS  Google Scholar 

  11. Eling TE, Thompson DC, Foureman GL, Curtis J, Hughes MF (1990) Prostaglandin H synthase and xenobiotic oxidation. Annu Rev Pharmacol Toxicol 30: 1–45

    PubMed  CAS  Google Scholar 

  12. Föllmann W, Hillebrand IE, Creppy EE, Bolt HM (1995) Sister chromatid exchange frequency in cultured isolated porcine urinary bladder epithelial cells (PUBEC) treated with ochratoxin A and alpha. Arch Toxicol 69: 280–286

    Article  PubMed  Google Scholar 

  13. Hald B (1991) Ochratoxin A in human blood in European countries. In: Castegnaro M, Plestina R, Dirheimer G, Chernozemsky IN, Bartsch H (eds) Mycotoxin, endemic nephropathy and urinary tract tumours. IARC Scientific Publications, vol. 115, International Agency for Research on Cancer, Lyon, pp 159–164

    Google Scholar 

  14. Holmberg T, Hagelberg S, Lundenheim N, Thafvelin B, Hult K (1990) Ochratoxin A in swine blood used for evaluation of cereal handling procedures. J Vet Med B 37: 97–105

    Article  CAS  Google Scholar 

  15. Hult K, Plestina R, Habazin-Novak V, Rodic B, Leovic S (1982) Ochratoxin A in human blood and Balkan endemic nephropathy. Arch Toxicol 51: 313–321

    Article  CAS  Google Scholar 

  16. Kanisawa M, Suzuki S (1978) Induction of renal and hepatic tumors in mice by ochratoxin A, a mycotoxin. Gann 69: 599–600

    PubMed  CAS  Google Scholar 

  17. Krogh P (1987) Ochratoxins in food. In: Krogh P (ed) Mycotoxins in food. Academic Press, London, pp 97–121

    Google Scholar 

  18. Kuiper-Goodman T, Scott PM (1989) Risk assessment of the mycotoxin ochratoxin A. Biomed Environ Sci 2: 179–248

    PubMed  CAS  Google Scholar 

  19. Liu L, Massey TE (1992) Bioactivation of aflatoxin B1 by lipoxygenases, prostaglandin H synthase and cytochrome P450 monooxygenase in guinea-pig tissues. Carcinogenesis 13: 533–539

    Article  PubMed  CAS  Google Scholar 

  20. Marnett LJ, Eling TE (1983) Cooxidation during prostaglandin biosynthesis: a pathway for the metabolic activation of xenobiotics. Rev Biochem Toxicol 5: 135–172

    CAS  Google Scholar 

  21. Merwe KJ van der, Steyn PS, Fourie L, Scott DB, Theron JJ (1965) Ochratoxin A, a toxic metabolite produced by Aspergillus ochraceus Wilh. Nature 205: 1112–1113

    Article  PubMed  Google Scholar 

  22. Moncada S, Vane JR (1979) Pharmacology and endogenous role of prostaglandin endoperoxides, thromboxane A2 and prostacyclin. Pharmacol Rev 30: 293–331

    Google Scholar 

  23. NTP (1988) Technical report on the toxicology and carcinogenesis studies of ochratoxin A (CAS No 303-47-9) in F344/N rats (gavage studies). NIH Publication No. 89-2813, US Dept of Health and Human Services, National Institutes of Health, Research Triangle Park, N. C.

    Google Scholar 

  24. Oster T, Jayyosi Z, Creppy EE, El Amri HS, Batt AM (1991) Characterization of pig liver purified cytochrome P450 isoenzymes for ochratoxin A metabolism studies. Toxicol Lett 57: 203–214

    Article  PubMed  CAS  Google Scholar 

  25. Petkova-Bocharova T, Chernozemsky IN, Castegnaro M (1988) Ochratoxin A in human blood in relation to Balkan endemic nephropathy and urinary system tumours in Bulgaria. Food Addit Contam 5: 299–301

    PubMed  CAS  Google Scholar 

  26. Pfohl-Leszkowicz A, Chakor K, Creppy EE, Dirheimer G (1991) DNA adduct formation in mice after treatment with ochratoxin A. In: Castegnaro M, Plestina H, Dirheimer G, Chernozemsky IN, Bartsch H (eds) Mycotoxin, endemic nephropathy and urinary tract tumours. IARC Science Publications, vol. 115, International Agency for Research on Cancer, Lyon, pp 245–254

    Google Scholar 

  27. Pfohl-Leszkowicz A, Grosse Y, Kane A, Creppy EE, Dirheimer G (1993a) Differential DNA adduct formation and disappearance in the mouse tissues after treatment with the mycotoxin ochratoxin A. Mutat Res 289: 265–273

    PubMed  CAS  Google Scholar 

  28. Pfohl-Leszkowicz A, Grosse Y, Kane A, Gharbi A, Baudrimont I, Obrecht S, Creppy EE, Dirheimer G (1993b) Is the oxidative pathway implicated in the genotoxicity of ochratoxin A? In: Creppy EE, Castegnaro M, Dirheimer G (eds) Human ochratoxicosis and its pathologies. Les Editions INSERM, vol. 231, John Libbey Eurotext, Montrouge, pp 177–187

    Google Scholar 

  29. Pfohl-Leszkowicz A, Grosse Y, Castegnaro M, Nicolov IG, Chernozemsky IN, Bartsch H, Betbeder AM, Creppy EE, Dirheimer G (1993c) Ochratoxin A-related DNA adducts in urinary tract tumours of Bulgarian subjects. In: Phillips DH, Castegnaro M, Bartsch H (eds) Postlabelling methods for detection of DNA adducts. IARC Scientific Publications, vol. 124, International Agency for Research on Cancer, Lyon, pp 141–148

    Google Scholar 

  30. Pfohl-Leszkowicz A, Obrecht S, Grosse Y, Dirheimer G (1994) Involvement of antioxidants and inhibitors of glutathione conjugation in ochratoxin A genotoxicity in mice liver and kidney. Toxicol Lett 74 [suppl 1]: 65

    Google Scholar 

  31. Pfohl-Leszkowicz A, Grosse Y, Obrecht S, Kane A, Castegnaro M, Creppy EE, Dirheimer G (1993d) Preponderance of DNA-adducts in kidney after ochratoxin A exposure. In: Creppy EE, Castegnaro M, Dirheimer G (eds) Human ochratoxicosis and its pathologies. Les Editions INSERM, vol. 231, John Libbey Eurotext, Montrouge, pp 199–207

    Google Scholar 

  32. Pohland AE (1993) Mycotoxins in review. Food Addit Contamin 10: 17–28

    CAS  Google Scholar 

  33. Pohland AE, Nesheim S, Friedman L (1992) Ochratoxin A: a review. Pure Appl Chem 64: 1029–1046

    Article  CAS  Google Scholar 

  34. Reddy V, Randerath J (1986) Nuclease P1-mediated enhancement of sensitivity of 32P-postlabelling test for structurally diverse DNA adducts. Carcinogenesis 7: 1543–1551

    Article  PubMed  CAS  Google Scholar 

  35. Sivarajah K, Lasker JM, Eling TE (1981) Prostaglandin synthetase-dependent cooxidation of (±)-benzo[a]pyrene-7,8-dihydrodiol by human lung and other mammalian tissues. Cancer Res 41: 1834–1839

    PubMed  CAS  Google Scholar 

  36. Smith WL, Marnett LJ (1991) Prostaglandin endoperoxide synthase: structure and catalyses. Biochim Biophys Acta 1083: 1–17

    PubMed  CAS  Google Scholar 

  37. Sostaric B, Vukelic M (1991) Characteristics of urinary tract tumours in the area of Balkan endemic nephropathy in Croatia. In: Castegnaro M, Plestina R, Dirheimer G, Chernozemsky IN, Bartsch H (eds) Mycotoxin, endemic nephropathy and urinary tract tumours. IARC Science Publication, vol. 115, International Agency for Research on Cancer, Lyon, pp 29–35

    Google Scholar 

  38. Speijers GJA, Egmond van HP (1993) Worldwide ochratoxin A levels in food and feeds. In: Creppy EE, Castegnaro M, Dirheimer G (eds) Human ochratoxicosis and its pathologies. Les Editions INSERM, vol. 231, John Libbey Eurotext, Montrouge, pp 85–100

    Google Scholar 

  39. Størmer FC (1992) Ochratoxin A, a mycotoxin of concern. In: Bhatnagar D, Lillehoj EB, Arora DK (eds) Mycotoxins in ecological systems. Handbook of Applied Mycology, Marcel Dekker, New York, pp 403–432

    Google Scholar 

  40. Ueno Y (1985) Biotransformation of mycotoxins in the reconstituted cytochrome P450 system. Proc Jpn Assoc Mycotox 22: 28–30

    CAS  Google Scholar 

  41. Zenser TV, Davis BB (1990) Oxidation of xenobiotics by prostaglandin H synthase. In: Goldstein RS, Hewitt WR, Hook JB (eds) Toxic interactions. Academic Press, San Diego, pp 61–86

    Google Scholar 

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Authors and Affiliations

  1. Unité de Recherche Propre du CNRS 9002 “Structure des Macromolécules Biologiques et Mécanismes de Reconnaissance”, Institut de Biologie Moléculaire et Cellulaire et Univesité L. Pasteur, 15 rue René Descartes, F-67084, Strasbourg, France

    S. Obrecht-Pflumio & G. Dirheimer

  2. Toxicologie et Sécurité Alimentaire, Ecole Nationale Supérieure Agronomique, 145 Avenue de Muret, F-31076, Toulouse, France

    Y. Grosse & A. Pfohl-Leszkowicz

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  1. S. Obrecht-Pflumio
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  2. Y. Grosse
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  3. A. Pfohl-Leszkowicz
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  4. G. Dirheimer
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Obrecht-Pflumio, S., Grosse, Y., Pfohl-Leszkowicz, A. et al. Protection by indomethacin and aspirin against genotoxicity of ochratoxin A, particularly in the urinary bladder and kidney. Arch Toxicol 70, 244–248 (1996). https://doi.org/10.1007/s002040050267

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  • DOI: https://doi.org/10.1007/s002040050267

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