Enzymatic Detoxication of Tumorigenic Bay-Region Diol-Epoxides of Polycyclic Aromatic Hydrocarbons by Conjugation with Glutathione

  • Bengt Jernström
  • Iain G. C. Robertson
  • Bengt Mannervik
  • Lennart Dock

Abstract

Polycyclic aromatic hydrocarbons (PAH), such as benzo(a)pyrene (BP), benz(a)anthracene (BA) and chrysene (C), are widely distributed contaminants in the environment and proven tumorigens in experimental animals. Epidemiological data indicate a role for PAH also in the etiology of certain human tumors1. PAH require metabolic transformation to electrophilic intermediates to exert their toxic effects, most probably through covalent binding of these intermediates to critical targets in DNA. BP is activated through the action of cytochrome P-450-linked monooxygenases and epoxide hydrolase to diastereomeric trans-7,8-dihydroxy-9,10-epoxy-7,8,9,10-tetrahydro-BP (anti- and syn-BPDE). The (+)-enantiomer of anti-BPDE, with R,S,S,R-absolute configuration, is the most tumorigenic one of the isomers in animals2. Similar results have been obtained with the equivalent diol-epoxides of BA and C3. Furthermore, covalent binding of (+)-anti-BPDE to the exocyclic nitrogen of deoxyguanosine in DNA of target tissues is closely correlated with tumor formation4. Thus, it is likely that enzymatic and non-enzymatic processes that prevent intracellular accumulation of PAH diol-epoxides will counteract DNA-damage and resulting consequences.

Keywords

Polycyclic Aromatic Hydrocarbon Epoxide Hydrolase Glutathione Transferase Polycyclic Hydrocarbon Reversed Phase Analytical Column 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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References

  1. 1.
    A. Dipple, Polyaromatic hydrocarbon carcinogenesis, in: “Polycyclic Hydrocarbons and Carcinogenesis”, R. G. Harvey, ed., American Chemical Society, Washington, D. C. (1985).Google Scholar
  2. 2.
    C. S. Cooper, P. L. Grover and P. Sims, The metabolism and activation of benzo(a)pyrene, Prog. Drug Metab. 7:295 (1983).Google Scholar
  3. 3.
    R. E. Lehr, S. Kumar, W. Levin, A. W. Wood, R. L. Chang, A. H. Conney, H. Yagi, J. M. Sayer and D. M. Jerina, The bay region theory of polycyclic aromatic hydrocarbon carcinogenesis, in: “Polycyclic Hydrocarbons and Carcinogenesis”, R. G. Harvey, ed., American Chemical Society, Washington, D. C. (1985).Google Scholar
  4. 4.
    J. C. Pelling, T. J. Slaga and J. DiGiovanni, Formation and persistence of DNA, RNA and protein adducts in mouse skin exposed to pure enantiomers of 7ß,8α-dihydroxy-9α,10α-epoxy-7,8,9,10-tetra-hydrobenzo(a)pyrene in vivo, Cancer Res. 44:1081 (1984).Google Scholar
  5. 5.
    B. Jernström, J. R. Babson, P. Moldéus, A. Holmgren and D. J. Reed, Glutathione conjugation and DNA-binding of (±)-trans-7,8-di-hydroxy-7,8-dihydrobenzo(a)pyrene and (±)-7ß,8α-dihydroxy-9α, 10α-epoxy-7,8,9,10-tetrahydrobenzo(a)pyrene in isolated rat hepatocytes, Carcinogenesis 3:861 (1982).PubMedCrossRefGoogle Scholar
  6. 6.
    B. Jernström, M. Martinez, S. Å, and L. Dock, Metabolism of benzo(a)pyrene-7,8-dihydrodiol and benzo(a)pyrene-7,8-dihydrodiol-9,10-epoxide to protein-binding products and glutathione conjugates in isolated hepatocytes, Carcinogenesis 5:1079 (1984).PubMedCrossRefGoogle Scholar
  7. 7.
    I. G. C. Robertson, H. Jensson, C. Guthenberg, M. K. Tahir, B. Jernström and B. Mannervik, Differences in the occurrence of glutathione transferase isoenzymes in rat lung and liver, Biochem Biophys Res Commun. 127:80 (1985).PubMedCrossRefGoogle Scholar
  8. 8.
    M. Warholm, C. Guthenberg, B. Mannervik and C. von Bahr, Purification of a new glutathione S-transferase (transferase μ) from human liver having high activity with benzo(a)pyrene-4,5-oxide, Biochem. Biophys. Res. Commun. 98:512 (1981).PubMedCrossRefGoogle Scholar
  9. 9.
    B. Mannervik and C. Guthenberg, Glutathione transferase (human placenta), Methods Enzymol. 77:231 (1981).PubMedCrossRefGoogle Scholar
  10. 10.
    W. B. Jakoby, B. Ketterer and B. Mannervik, Glutathione transferases: nomenclature, Biochem. Pharmacol. 33:2539 (1984).PubMedCrossRefGoogle Scholar
  11. 11.
    I. G. C. Robertson and B. Jernström, The enzymatic conjugation of glutathione with bay-region diol-epoxides of benzo(a)pyrene, benz(a)anthracene, and chrysene, Carcinogenesis 7:1633 (1986).PubMedCrossRefGoogle Scholar
  12. 12.
    I. G, C. Robertson, H. Jensson, B. Mannervik and B. Jernström, Glutathione transferases in rat lung: the presence of transferase 7–7, highly efficient in the conjugation of glutathione with the carcinogenic (+)-7ß,-8α-dihydroxy-9α,10α-oxy-7,8,9,10-tetrahydro-benzo(a)pyrene, Carcinogenesis 7:295 (1986).PubMedCrossRefGoogle Scholar
  13. 13.
    I. G. C. Robertson, C. Guthenberg, B. Mannervik and B. Jernström, Differences in stereoselectivity and catalytic efficiency of three human glutathione transferases in the conjugation of glutathione with 7ß,8α-dihydroxy-9α,10α-oxy-7,8,9,10-tetrahydrobenzo-(a)pyrene, Cancer Res. 46:2220 (1986).PubMedGoogle Scholar
  14. 14.
    L. Dock, M. Martinez and B. Jernström, Increased stability of (±)-7ß,8α-dihydroxy-9α,10α-epoxy-7,8,9,10-tetrahydrobenzo(a)pyrene through interaction with subcellular fraction of rat liver, Chem.-Biol. Interact. 61:31 (1987).PubMedCrossRefGoogle Scholar
  15. 15.
    B. Jernström, M. Martinez, D. J. Meyer and B. Ketterer, Glutathione conjugation of the carcinogenic and mutagenic electrophile (±)-7ß,8α-dihydroxy-9α, 10α-oxy-7,8,9,10-tetrahydrobenzo(a)pyrene catalyzed by purified rat liver glutathione transferases, Carcinogenesis 6:85 (1985).PubMedCrossRefGoogle Scholar
  16. 16.
    S. K. Yang, D. W. McCourt, P. P. Roeler and H. V. Gelboin, Enzymatic conversion of benzo(a)pyrene leading predominantly to the diolepoxide r-7,t-8-dihydroxy-t-9,10-oxy-7,8,9,10-tetrahydrobenzo(a)-pyrene through a single enantiomer of r-7,t-8-dihydroxy-7,8-di-hydrobenzo(a)pyrene, Proc. Natl. Acad. Sci. USA 73:2594 (1976).PubMedCrossRefGoogle Scholar
  17. 17.
    B. Mannervik, The isoenzymes of glutathione transferase, Adv Enzymol. 57:357 (1985).PubMedGoogle Scholar
  18. 18.
    M. Warholm, C. Guthenberg and B. Mannervik, Molecular and catalytic properties of glutathione transferase μ from human liver: an enzyme efficiently conjugating epoxides, Biochemistry 22:3610 (1983).PubMedCrossRefGoogle Scholar
  19. 19.
    J.-E. Seidegård, R. W. Pero, D. G. Miller and E. J. Beattie, A glutathione transferase in human leukocytes as a marker for the susceptibility to lung cancer, Carcinogenesis 7:751 (1986).PubMedCrossRefGoogle Scholar
  20. 20.
    T. D. Boyer, D. Zakim and D. A. Vessey, Do soluble glutathione Stransferase have direct access to membrane-bound substrates? Biochem. Pharmacol. 32:29 (1983).PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1988

Authors and Affiliations

  • Bengt Jernström
    • 1
  • Iain G. C. Robertson
    • 2
  • Bengt Mannervik
    • 3
  • Lennart Dock
    • 4
  1. 1.Department of ToxicologyKarolinska InstitutetStockholmSweden
  2. 2.Department of Pharmacology and Clinical PharmacologyUniversity of AucklandAucklandNew Zealand
  3. 3.Department of BiochemistryArrhenius Laboratory University of StockholmStockholmSweden
  4. 4.National Institute of Environmental MedicineStockholmSweden

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