Role of the Well-Known Basic and the Recently Discovered Acidic Glutathione S-Transferases in the Control of Genotoxic Metabolites

  • Franz Oesch
  • Ingolf Gath
  • Takashi Igarashi
  • Hansruedi Glatt
  • Helmut Thomas
Part of the NATO ASI Series Advanced Science Institutes Series book series (NSSA, volume 202)


Glutathione S-transferases (GSTs; E.C. 2. 5. 1. 18) are a family of enzymes which have increasingly attracted the interest of toxicologists, pharmacologists, biochemists and clinicians since their discovery in 1961 (1). Initially, GSTs were believed to serve as intracellular transport proteins for endogenous compounds with limited solubility in water, thus acting as an intracellular equivalent to albumin in blood plasma. In this assumed capacity of reversible binding and transport of various ligands, the corresponding protein was named ligandin (2). Following the discovery of abundant GST occurrence in most forms of aerobic life including plants, and the GST-catalysed conjugation of a wide variety of elec-trophilic substrates with glutathione, GSTs are now generally considered to play a crucial role in the detoxification of foreign compounds such as mutagens, carcinogens and other noxious chemicals (for reviews see Refs. 3–6) by conjugation to glutathione. In addition, GSTs are believed to provide cellular protection by covalent binding of reactive electrophiles to the enzyme, which results in immobilization and inactivation of the compound in question.


Polycyclic Aromatic Hydrocarbon Glutathione Transferase Ethacrynic Acid Cumene Hydroperoxide Microsomal Epoxide Hydrolase 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    J. Booth, E. Boyland and P. Sims, An enzyme from rat liver catalysing conjugations with glutathione. Biochem. J., 79: 516–526 (1961).PubMedGoogle Scholar
  2. 2.
    G. Litwack, B. Ketterer and I. M. Arias, Ligandin: a hepatic protein which binds steroids, bilirubin, carcinogens and a number of organic anions, Nature (London), 234: 466–467 (1971).CrossRefGoogle Scholar
  3. 3.
    B. Mannervik, The isoenzyme of glutathione transferase, Adv. Enzymol. Rel. Areas Mol. Biol., 57: 357–417 (1985).Google Scholar
  4. 4.
    B. Ketterer, Protective role of glutathione and glutathione transfer-ases in mutagenesis and carcinogenesis, Mutat. Res., 202: 343–361 (1988).PubMedCrossRefGoogle Scholar
  5. 5.
    B. Mannervik and U. H. Danielson, Glutathione transferases-structure and catalytic activity, CRC Crit. Rev. Biochem., 23: 283–337 (1988).PubMedCrossRefGoogle Scholar
  6. 6.
    H. Sies and B. Ketterer (eds), Glutathione conjugation: mechanisms and biological significance, Academic Press, New York (1988).Google Scholar
  7. 7.
    T. Igarashi, T. Satoh, K. Ueno and H. Kitagawa, Species difference in glutathione level and glutathione related enzyme activities in rats, mice, guinea pigs and hamsters, J. Pharm. Dyn., 6: 941–949 (1983).CrossRefGoogle Scholar
  8. 8.
    T. Igarashi, N. Tomihari, S. Ohmori, K. Ueno, H. Kitagawa and T. Satoh, Comparison of glutathione S-transferases in mouse, guinea pig, rabbit and hamster liver cytosol to those in rat liver, Biochem. International, 13: 641–648 (1986).Google Scholar
  9. 9.
    A. A. Fryer, R. Hume and R. C. Strange, The development of glutathione S-transferase and glutathione peroxidase activities in human lung, Biochim. Biophys. Acta., 883: 448 (1986).PubMedCrossRefGoogle Scholar
  10. 10.
    C. G. Faulder, P.A. Hirrell, R. Hume and R. C. Strange, Studies of the development of basic, neutral and acidic isoenzymes of glutathione S-transferases in human liver, adrenal, kidney and spleen, Biochem. J., 241: 221–228 (1987).PubMedGoogle Scholar
  11. 11.
    T. Igarashi, T. Satoh, K. Iwashita, S. Ono, K. Ueno and H. Kitagawa, Sex difference in subunit composition of hepatic glutathione S-trans-ferase in rats, J. Biochem., 98: 117–123 (1985).PubMedGoogle Scholar
  12. 12.
    I. Hatayama, K. Satoh and K. Sato, Development and hormonal regulation of the major form of hepatic glutathione S-transferase in male mice, Biochem. Biophys. Res. Commun., 140: 581–588 (1986).PubMedCrossRefGoogle Scholar
  13. 13.
    K. Sato, Glutathione transferases as markers of preneoplasia and neoplasia, Adv. Cancer Res., 52: 205–255 (1989).PubMedCrossRefGoogle Scholar
  14. 14.
    C. A. Telakowski-Hopkins, R. G. King and C. B. Pickett, Glutathione S-transferase Ya subunit gene: identification of regulatory elements required for basal level and inducible expression, Proc. Natl. Acad. Sci. USA, 85: 1000–1004 (1988).PubMedCrossRefGoogle Scholar
  15. 15.
    C. B. Pickett, C. A. Telakowski-Hopkins, G. J. F. Ding, L. Argenbright and A. Y. H. Lu, Rat liver glutathione S-transferases. Complete nucleotide sequence of a glutathione S-transferase mRNA and the regulation of the Ya, Yb, and Yc mRNA by 3-methylcholanthrene and phenobarbital, J. Biol. Chem., 259: 5182–5188 (1984).PubMedGoogle Scholar
  16. 16.
    C. A. Telakowski-Hopkins, G. S. Rothkopf and C. B. Pickett, Structural analysis of a rat liver glutathione S-transferase Ya gene, Proc. Natl. Acad. Sci. USA, 83: 9393–9397 (1986).PubMedCrossRefGoogle Scholar
  17. 17.
    G. J. F. Ding, A. Y. H. Lu and C. B. Pickett, Rat liver glutathione S-transferases. Nucleotide sequence analysis of a Ybl cDNA clone and prediction of the complete amino acid sequence of the Ybl subunit, J. Biol. Chem., 260: 13268–13271 (1985).PubMedGoogle Scholar
  18. 18.
    G. J. F. Ding, V. D. H. Ding, J. A. Rodkey, C. D. Bennett, A. Y. H. Lu and C. B. Pickett, Rat liver glutathione S-transferases. DNA sequence analysis of a Yb2 cDNA clone and regulation of the Ybl and Yb2 mRNAs by phenobarbital, J. Biol. Chem., 261: 7952–7957 (1986).PubMedGoogle Scholar
  19. 19.
    Y. Suguoka, T. Kano, A. Okuda, M. Sakai, T. Kitagawa and M. Muramatsu, Cloning and the nucleotide sequence of rat glutathione S-transferase P cDNA, Nucleic Acids Res., 13: 6049–6057 (1985).PubMedCrossRefGoogle Scholar
  20. 20.
    H. Jensson, C. Guthenberg, P. AT in and B. Mannervik, Rat glutathione transferase 8-8, an enzyme efficiently detoxifying 4-hydroxyalk-2-enals, FEBS Lett., 203: 207–209 (1986).PubMedCrossRefGoogle Scholar
  21. 21.
    P. Alin, H. Danielson and B. Mannervik, 4-Hydroxy-alk-2-enals are substrates for glutathione transferase, FEBS Lett., 179: 267–270 (1985).PubMedCrossRefGoogle Scholar
  22. 22.
    B. Coles, D. J. Meyer, B. Ketterer, C. A. Stanton and R. C. Garner, Studies on the detoxication of microsomally-activated aflatoxin Bl by glutathione and glutathione S-transferases in vitro, Carcinogenesis, 6: 693–697 (1985).PubMedCrossRefGoogle Scholar
  23. 23.
    T. Igarashi, N. Irokawa, S. Ono, S. Ohmori, K. Ueno and H. Kitagawa, Difference in the effects of phenobarbital and 3-methylcholanthrene treatment on subunit composition of hepatic glutathione S-transferases in male and female rats, Xenobiotica, 17: 127–137 (1987).PubMedCrossRefGoogle Scholar
  24. 24.
    Z. Gregus, C. Madhu and C. D. Klaasen, Inducibility of glutathione S-transferases in hamsters, Cancer Lett., 44: 89–94 (1989).PubMedCrossRefGoogle Scholar
  25. 25.
    D. R. Thakker, H. Yagi, W. Levin, A. W. Wood, A. H. Conney and D. M. Jerina, Polycyclic aromatic hydrocarbons: metabolic activation to ultimate carcinogens. In: M. W. Anders (ed.): “Bioactivation of Foreign Compounds”, New York: Academic Press, pp. 177–242 (1985).Google Scholar
  26. 26.
    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: 85–89 (1985).PubMedCrossRefGoogle Scholar
  27. 27.
    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-tetrahydrobenzo(a)pyre-ne, Carcinogenesis, 7: 295–299 (1986).PubMedCrossRefGoogle Scholar
  28. 28.
    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,10 α-oxy-7, 8, 9, 10-tetrahydrobenzo(a)pyrene, Cancer Res., 46: 2220–2224 (1986).PubMedGoogle Scholar
  29. 29.
    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: 1633–1636 (1986).PubMedCrossRefGoogle Scholar
  30. 30.
    T. Friedberg, U. Milbert, P. Bentley, T. M. Guenthner and F. Oesch, Purification and characterization of a new cytosolic glutathione S-transferase (glutathione S-transferase X) from rat liver, Biochem. J. 215: 617–625 (1983).PubMedGoogle Scholar
  31. 31.
    H. Glatt, T. Friedberg, P. L. Grover, P. Sims and F. Oesch, Inactiva-tion of a diol epoxide and a K-region epoxide with high efficiency by glutathione transferase X, Cancer Res., 43: 5713–5717 (1983).PubMedGoogle Scholar
  32. 32.
    U. Milbert, Ph.D.-Thesis, University of Mainz (1986).Google Scholar
  33. 33.
    H. R. Glatt, C. S. Cooper, P. L. Grover, P. Sims, P. Bentley P, I. Merdes, F. Waechter, K. Vogel, T. M. Guenthner and F. Oesch, Inactiva-tion of a diol-epoxide by dihydrodiol dehydrogenase, but not by two epoxide hydrolases, Science, 215: 1507–1509 (1982).PubMedCrossRefGoogle Scholar
  34. 34.
    W. B. Jakoby, B. Ketterer and B. Mannervik, Glutathione transferases: nomenclature, Biochem. Pharmacol., 33: 2539–2540 (1984).PubMedCrossRefGoogle Scholar
  35. 35.
    W. B. Jakoby, W. H. Habig, J. H. Keen, J. N. Ketley and M. J. Pabst, Glutathione S-transferases: catalytical aspects. In: I. M. Arias and W. B. Jakoby (eds.): “Glutathione: Metabolism and Function”, New York: Raven Press, pp. 189–201 (1976).Google Scholar
  36. 36.
    W. H. Habig, M. J. Pabst and W. B. Jakoby, Glutathione S-transferases. The first enzymatic step in mercapturic acid formation, J. Biol. Chem., 249: 7130–7139 (1974).PubMedGoogle Scholar
  37. 37.
    B. Gilham, The reaction of aralkyl sulphate esters with glutathione catalysed by rat liver preparations, Biochem. J., 121: 667–672 (1971).Google Scholar

Copyright information

© Plenum Press, New York 1991

Authors and Affiliations

  • Franz Oesch
    • 1
  • Ingolf Gath
    • 1
  • Takashi Igarashi
    • 1
  • Hansruedi Glatt
    • 1
  • Helmut Thomas
    • 1
  1. 1.Institute of ToxicologyUniversity of Mainz Obere Zahlbacher Strasse 67MainzGermany

Personalised recommendations