Epoxide Hydrolase Isoenzymes and their Individual Contribution to the Control of Toxic Metabolites

  • Franz Oesch
  • Ludwig Schladt
  • Michael Knehr
  • Johannes Döhmer
  • Helmut Thomas
Part of the NATO ASI Series Advanced Science Institutes Series book series (NSSA, volume 202)


Epoxides are highly strained three membered cyclic ethers which are formed in vivo by the microsomal cytochrome P450 dependent monooxygenases as intermediates of several important biosynthetic pathways (leukotriene A4, squalene 2, 3-oxide) and as metabolites of numerous xenobiotic compounds containing olefinic or aromatic double bonds. Further transformation of these epoxides may occur by either, rearrangement to phenols, aliphatic aldehydes, or ketones; by cytochrome P450 dependent reduction to the parent compound; or by spontaneous or enzymatic conjugation to gluta-thione. Epoxides may also bind covalently to cellular nucleophiles, such as proteins and nucleic acids thus eliciting carcinogenic, mutagenic and other toxic effects.


Polycyclic Aromatic Hydrocarbon Epoxide Hydrolase Styrene Oxide Hyperplastic Nodule Microsomal Epoxide Hydrolase 
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.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    P. Bentley, F. Oesch and H. Glatt, Dual role of epoxide hydratase in both activation and inactivation of benzo(a)pyrene, Arch. Toxicol., 39: 65–75 (1977).PubMedCrossRefGoogle Scholar
  2. 2.
    E. Boyland, The biological significance of the metabolism of polycyclic compounds, Biochem. Soc. Symp., 5: 40–54 (1950).Google Scholar
  3. 3.
    H. Breuer and R. Knuppen, The formation and hydrolysis of 16α,17α-ep-oxy-oestratriene-3-ol by rat liver tissue. Biochim. Biophys. Acta, 49: 620–621 (1961).CrossRefGoogle Scholar
  4. 4.
    T. Watabe and E. W. Maynert, Role of epoxides in the metabolism of olefins, Pharmacologist, 10: 203 (1968).Google Scholar
  5. 5.
    F. Oesch, N. Kaubisch, D. M. Jerina and J. W. Daly, Hepatic epoxide hydrase: structure activity relationships for substrates and inhibitors, Biochemistry, 10: 4858–4866 (1971).PubMedCrossRefGoogle Scholar
  6. 6.
    T. Watabe and S. Kanehira, Solubilisation of epoxide hydrolase from liver microsomes, Chem. Pharm. Bull. (Tokyo), 18: 1295–1296 (1970).CrossRefGoogle Scholar
  7. 7.
    P. Bentley and F. Oesch, Purification of rat liver epoxide hydratase to apparent homogeneity, FEBS Lett., 59: 291–295 (1975).PubMedCrossRefGoogle Scholar
  8. 8.
    A. Y. H. Lu, D. Ryan, D. M. Jerina, J. W. Daly and W. Levin, Liver microsomal epoxide hydrolase: solubilisation, purfication and characterization, J. Biol. Chem., 250: 8283–8288 (1975).PubMedGoogle Scholar
  9. 9.
    S. S. Gill, B. D. Hammock and J. E. Casida, Mammalian metabolism and environmental degradation of the juvenoid l-(4-ethylphenoxy)-3,7-di-methyl-6, 7-epoxy-trans-2-octene and related compounds, J. Agr. Food Chem., 22: 386–395 (1974).CrossRefGoogle Scholar
  10. 10.
    F. Waechter, M. Merdes, F. Bieri, W. Stäubli and P. Bentley, Purification and characterization of a soluble epoxide hydratase from rabbit liver. Eur. J. Biochem. 125: 457–461 (1982).PubMedCrossRefGoogle Scholar
  11. 11.
    P. Wang, J. Meijer and F. P. Guengerich, Purification of human liver cytosolic epoxide hydrolase and comparison to the microsomal enzyme, Biochemistry, 21: 5769–5776 (1982).PubMedCrossRefGoogle Scholar
  12. 12.
    T. Watabe, M. Kanai, M. Jsobe and N. Ozawa, The hepatic microsomal biotransformation of A-steroids to 5α,6ß-glycols via α-and ß-ep-oxides. J. Biol. Chem. 256: 2900–2907 (1981).PubMedGoogle Scholar
  13. 13.
    F. Oesch, C. W. Timms, C. H. Walker, T. M. Guenthner, A. Sparrow, T. Watabe, and C. R. Wolf, Existence of multiple forms of microsomal epoxide hydrolases with radically different substrate specificities, Carcinogenesis, 5: 7–9 (1984).PubMedCrossRefGoogle Scholar
  14. 14.
    J. McGee and F. Fitzpatrick, Enzymatic hydration of leukotriene A.: Purification and characterization of a novel epoxide hydrolase from human erythrocytes, J. Biol. Chem., 260: 12832–12837 (1985).PubMedGoogle Scholar
  15. 15.
    F. P. Guengerich, Epoxide hydrolase: properties and metabolic roles, in: “Reviews in Biochemical Toxicology”, Vol. 4, E. Hodgson, J. R. Bend and R. M. Philpot, eds., Elsevier Science Publishing Company, New York, 5–30 (1982).Google Scholar
  16. 16.
    R. N. Wixtrom and B. D. Hammock, Membrane-bound and soluble-fraction epoxide hydrolases: methodological aspects, in: “Biochemical Pharmacology and Toxicology”, Vol. 1, D. Zakim and D. A. Vessey, eds., John Wiley and Sons, New York, 1–93 (1985).Google Scholar
  17. 17.
    J. Meijer and J. W. De Pierre, Cytosolic epoxide hydrolase, Chem.-Biol. Interactions, 64: 207–249 (1988).CrossRefGoogle Scholar
  18. 18.
    F. S. Heinemann and J. Ozols, The covalent structure of hepatic microsomal epoxide hydrolase, J. Biol. Chem., 259: 791–804 (1984).PubMedGoogle Scholar
  19. 19.
    T. D. Porter, T. W. Beck and C. B. Kasper, Complementary DNA and amino acid sequence of rat liver microsomal, xenobiotic epoxide hydrolase, Arch. Biochem. Biophys., 248: 121–129 (1986).PubMedCrossRefGoogle Scholar
  20. 20.
    R. C. Skoda, A. Demierre, O. W. McBride, F. J. Gonzalez and U. A. Meyer, Human microsomal xenobiotic epoxide hydrolase: Complementary DNA sequence, complementary DNA-directed expression in COS-1 cells, and chromosomal localization, J. Biol. Chem., 263: 1549–1554 (1988).PubMedGoogle Scholar
  21. 21.
    C. D. Funk, O. Rådmark, J. Y. Fu, T. Matsumoto, H. Jörnvall, T. Shimizu, and B. Samuelsson. Molecular cloning and amino acid seqence of leukotriene A4 hydrolase, Proc. Natl. Acad. Sci. USA, 84: 6677–6681 (1987).PubMedCrossRefGoogle Scholar
  22. 22.
    J. Seidegård and J. W. DePierre, Microsomal epoxide hydrolase: properties, regulation and function, Biochim. Biophys. Acta, 695: 251–270 (1983).PubMedGoogle Scholar
  23. 23.
    A. Åström, M. Eriksson, L. C. Eriksson, W. Birberg, A. Pilotti, and J. W. DePierre, Subcellular and organ distribution of cholesterol epoxide hydrolase in rat, Biochim. Biophys. Acta, 882: 359–366 (1986).PubMedCrossRefGoogle Scholar
  24. 24.
    M. H. Silva and B. D. Hammock, Affinity purification of cytosolic epoxide hydrolase from human, rhesus monkey, baboon, rabbit, rat and mouse liver, Comp. Biochem. Physiol., 87B: 95–102 (1987).Google Scholar
  25. 25.
    F. P. Guengerich, P. Wang, M. B. Mitchell, and P. S. Mason, Rat and human liver microsomal epoxide hydrolase: purification and evidence of multiple forms, J. Biol. Chem., 254: 12248–12254 (1979).PubMedGoogle Scholar
  26. 26.
    N. J. Bulleid, A. B. Graham and J. A. Craft, Microsomal epoxide hydrolase of rat liver: Purification and characterization of enzyme fractions with different Chromatographic characteristics, Biochem. J., 233: 607–611 (1986).PubMedGoogle Scholar
  27. 27.
    D. E. Moody and B. D. Hammock, Purification of microsomal epoxide hydrolase from liver of rhesus monkey: partial separation of ois-and trans-stilbene oxide hydrolase, Arch. Biochem. Biophys., 258: 156–166 (1987).PubMedCrossRefGoogle Scholar
  28. 28.
    L. Schladt, H. Thomas, R. Hartmann and F. Oesch, human liver cytosolic epoxide hydrolases, Eur. J. Biochem., 176: 715–723 (1988).PubMedCrossRefGoogle Scholar
  29. 29.
    C. N. Falany, P. McQuiddy and C. B. Kasper, Structure and organization of the microsomal xenobiotic epoxide hydrolase gene, J. Biol. Chem., 262: 5924–5930 (1987).PubMedGoogle Scholar
  30. 30.
    P. E. Thomas, L. M. Reik, D. E. Ryan and W. Levin, Regulation of three forms of cytochrome P450 and epoxide hydrolase in rat liver micro-somes, J. Biol. Chem., 256: 1044–1052 (1981).PubMedGoogle Scholar
  31. 31.
    F. Oesch F, Mammalian epoxide hydrases: inducible enzymes catalysing the inactivation of carcinogenic and cytotoxic metabolites derived from aromatic and olefinic compounds, Xenobiotica, 3: 305–340 (1973).PubMedCrossRefGoogle Scholar
  32. 32.
    F. Oesch, Differential control of rat microsomal aryl hydrocarbon monooxygenase and epoxide hydratase, J. Biol. Chem., 251: 79–87 (1976).PubMedGoogle Scholar
  33. 33.
    J. A. Craft, N. J. Buileid, M. R. Jackson and B. Burchell, Induction of microsomal epoxide hydrolase by nitrosamines in rat liver, Bio-chem. Pharmacol., 37: 297–302 (1988).CrossRefGoogle Scholar
  34. 34.
    A. Y. H. Lu and G. T. Miwa, Molecular properties and biological functions of microsomal epoxide hydrase, Ann. Rev. Pharmacol. Toxicol., 20: 513–531 (1980).CrossRefGoogle Scholar
  35. 35.
    P. P. Halarnkar, R.N. Wixtröm, M. H. Silva and B. D. Hammock, Cata-bolism of epoxy fatty esters by the purified epoxide hydrolase form mouse and human liver, Arch. Biochem. Biophys., 272: 226–236 (1989).PubMedCrossRefGoogle Scholar
  36. 36.
    R. N. Armstrong, B. Kedzierski, W. Levin and D. M. Jerina, Enantio-selectivity of microsomal epoxide hydrolase toward arene oxide substrates, J. Biol. Chem., 256: 4726–4733 (1981).PubMedGoogle Scholar
  37. 37.
    G. D. Prestwich, I. Lucarelli, S.-K. Park, D. N. Loury, D. E. Moddy and B. D. Hammock, Cyclopropyl oxiranes: reversible inhibitors of cytosolic and microsomal epoxide hydrolases, Arch. Biochem. Biophys., 237: 361–372 (1985).PubMedCrossRefGoogle Scholar
  38. 38.
    G. D. Prestwich, J.-W. Kuo, S.-K. Park, D.N. Loury, and B. D. Hammock, Inhibition of epoxide metabolism by α,ß-epoxyketones and isosteric analogs, Arch. Biochem. Biphys., 242: 11–15 (1985).CrossRefGoogle Scholar
  39. 39.
    F. Oesch and J. Daly, Conversion of naphthalene to trans-naphthalene dihydrodiol: evidence for the presence of a coupled aryl monooxygen-ase-epoxide hydrase system in hepatic microsomes, Biochem. Biophys. Res. Commun., 46: 1713–1720 (1972).PubMedCrossRefGoogle Scholar
  40. 40.
    W. Levin, A. Y. H. Lu, P. E. Thomas, D. Ryan, D. E. Kizer and M. J. Griffin, Identification of epoxide hydrase as the preneoplastic antigen in rat liver hyperplastic nodules, Proc. Natl. Acad. Sci. USA, 75: 3240–3243 (1978).PubMedCrossRefGoogle Scholar
  41. 41.
    M. J. Griffin and K. Noda, Quantisation of epoxide hydrolase released from hyperplastic nodule and hepatoma microsomes, Cancer Res., 40: 2768–2773 (1980).PubMedGoogle Scholar
  42. 42.
    H. Haymerle, J. Herz, G. M. Bressan, R. Frank, and K. K. Stanley, Efficient construction of cDNA libraries in plasmid expression vectors using an adaptor strategy, Nuci. Acids Res., 14: 8615–8624 (1986).CrossRefGoogle Scholar
  43. 43.
    L. Schladt, R. Hartmann, W. Wörner, H. Thomas and F. Oesch, Purification and characterization of rat-liver cytosolic epoxide hydrolase, Eur. J. Biochem., 176: 31–37 (1988).PubMedCrossRefGoogle Scholar
  44. 44.
    J. Meijer, G. Lundqvist and J. W. DePierre, Comparison of the sex and subcellular distributions, catalytic and immunochemical reactivities of hepatic epoxide hydrolases in seven mammalian species, Eur. J. Biochem., 167: 269–279 (1987).PubMedCrossRefGoogle Scholar
  45. 45.
    C. R. Pace-Asciak and W.S. Lee WS, Purification of hepoxilin epoxide hydrolase from rat liver, J. Biol. Chem., 264: 9310–9313 (1989).PubMedGoogle Scholar
  46. 46.
    S. S. Gill, Purification of mouse liver cytosolic epoxide hydrolase, Biochim. Biophys. Acta, 112: 763–769 (1983).Google Scholar
  47. 47.
    J. Meijer and J. W. DePierre, Properties of cytosolic epoxide hydrolase purified from the liver of untreated and clofibrate-treated mice. Characterization of optimal assay conditions, substrate specificity and effects of modulators on the catalytic activity, Eur. J. Biochem., 150: 7–16 (1985).PubMedCrossRefGoogle Scholar
  48. 48.
    S. S. Gill, Immunological similarity of epoxide hydrolase activity in the mitochondrial and cytosolic fractions of mouse liver, Biochem. Biophys. Res. Commun., 122: 1434–1440 (1984).PubMedCrossRefGoogle Scholar
  49. 49.
    U. Milbert, W. Wörner and F. Oesch, Characterization of rat hepatic and renal glutathione S-transferases, in: “Primary Changes and Control Factors in Carcinogenesis”, T. Friedberg and F. Oesch, eds., Deutscher Fachschriften-Verlag, Wiesbaden, 14–21 (1986).Google Scholar

Copyright information

© Plenum Press, New York 1991

Authors and Affiliations

  • Franz Oesch
    • 1
  • Ludwig Schladt
    • 1
  • Michael Knehr
    • 1
  • Johannes Döhmer
    • 1
  • Helmut Thomas
    • 1
  1. 1.Institute of ToxicologyUniversity of Mainz Obere Zahlbacher Straße 67MainzGermany

Personalised recommendations