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

  • Franz Oesch
  • Ingolf Gath
  • Takashi Igarashi
  • Hansruedi Glatt
  • Barbara Oesch-Bartlomowicz
  • Helmut Thomas
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 283)


The discovery of glutathione S-transferases (GSTs; E.C. active in the metabolism of carcinogens dates back to Booth et al. (1961). GSTs were initially believed to serve as intracellular transport proteins for endogenous compounds with limited solubility in water, thereby acting as an intracellular equivalent to albumin. In this assumed capacity of reversible binding and transport of various ligands, the corresponding protein was named ligandin (Litwack et al., 1971). Following the discovery of abundant GST occurrence in most forms of arerobic life including plants, and the GST-catalysed conjugation of a wide variety of electrophilic substrates with glutathione, GSTs are now generally considered to play a crucial role in the detoxification of foreign compounds (for reviews see Mannervik, 1985; Ketterer, 1988; Mannervik and Danielson, 1988; Sies and Ketterer, 1988). GSTs are also believed to provide cellular protection by covalent binding of reactive electrophiles to the enzyme itself resulting in immobilization and inactivation of the compound.


Polycyclic Aromatic Hydrocarbon Glutathione Transferase Ethacrynic Acid Cumene Hydroperoxide Diol Epoxide 
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  1. Alin, P., Danielson, H., and Mannervik, B. (1985). 4-Hydroxy-alk-2-enals are substrates for glutathione transferase. FEBS Lett. 179, 267–270.CrossRefPubMedGoogle Scholar
  2. Booth, J., Boyland, E. and Sims, P. (1961). An enzyme from rat liver catalysing conjugations with glutathione. Biochem. J. 79, 516–526.PubMedGoogle Scholar
  3. Coles, B., Meyer, D.J., Ketterer, B., Stanton, C.A., and Garner, R.C. (1985). Studies on the detoxication of microsomally-activated afla-toxin B1 by glutathione and glutathione S-transferases in vitro. Carcinogenesis 6, 693–697.CrossRefGoogle Scholar
  4. Ding, G.J.F., Ding, V.D.H., Rodkey, J.A., Bennett, C.D., Lu, A.Y.H., and Pickett, C.B. (1986). 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.PubMedGoogle Scholar
  5. Ding, G.J.F., Lu, A.Y.H., and Pickett, C.B. (1985). Rat liver glutathione Stransferases. 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.PubMedGoogle Scholar
  6. Faulder, C.G., Hirrell, P.A., Hume, R., and Strange, R.C. (1987). Studies of the development of basic, neutral and acidic isoenzymes of glutathione Stransferases in human liver, adrenal, kidney and spleen. Biochem. J. 241, 221–228.PubMedGoogle Scholar
  7. Friedberg, T., Milbert, U., Bentley, P., Guenthner, T.M. and Oesch, F. (1983). Purification and characterization of a new cytosolic glutathione S-transferase (glutathione S-transferase X) from rat liver. Biochem. J. 215, 617–625.PubMedGoogle Scholar
  8. Fryer, A.A., Hume, R., and Strange, R.C. (1986). The development of glutathione Stransferase and glutathione peroxidase activities in human lung. Biochim. Biophys. Acta. 883, 448.Google Scholar
  9. Gilham, B. (1971). The reaction of aralkyl sulphate esters with glutathione catalysed by rat liver preparations. Biochem. J. 121, 667–672.Google Scholar
  10. Glatt, H.R., Cooper, C.S., Grover, P.L., Sims, P., Bentley, P., Merdes, I., Waechter, F., Vogel, K., Guenthner, T.M. and Oesch, F. (1982). Inactivation of a diol-epoxide by dihydrodiol dehydrogenase, but not by two epoxide hydrolases. Science 215, 1507–1509.CrossRefPubMedGoogle Scholar
  11. Glatt, H.R., Friedberg, T., Grover, P.L., Sims, P. and Oesch, F. (1983). Inactivation of a diol epoxide and a K-region epoxide with high efficiency by glutathione transferase X. Cancer Res. 43, 5713–5717.PubMedGoogle Scholar
  12. Gregus, Z., Madhu, C., and Klaasen, C.D. (1989). Inducibility of glutathione Stranserases in hamsters. Cancer Lett. 44, 89–94.CrossRefPubMedGoogle Scholar
  13. Habig, W.H., Pabst, M.J. and Jakoby, W.B. (1974). Glutathione S-transferases. The first enzymatic step in mercapturic acid formation. J. Biol. Chem. 249, 7130–7139.PubMedGoogle Scholar
  14. Hatayama, I., Satoh, K., and Sato, K. (1986). Development and hormonal regulation of the major form of hepatic glutathione S-transferase in male mice. Biochem. Biophys. Res. Comun. 140, 581–588.CrossRefGoogle Scholar
  15. Igarashi, T., Irokawa, N., Ono, S., Ohmori, S., Ueno, K., and Kitagawa, H. (1987). Difference in the effects of phenobarbital and 3-methylchol-anthrene treatment on subunit composition of hepatic glutathione S-transferases in male and female rats. Xenobiotica 17, 127–137.CrossRefPubMedGoogle Scholar
  16. Igarashi, T., Satoh, T., Ueno, K., and Kitagawa, H. (1983). Species difference in glutathione level and glutathione related enzyme activities in rats, mice, guinea pigs and hamsters. J. Pharm. Dyn. 6, 941–949.CrossRefGoogle Scholar
  17. Igarashi, T., Satoh, T., Iwashita, K., Ono, S., Ueno, K., and Kitagawa, H. (1985). Sex difference in subunit composition of hepatic glutathione S-transferase in rats. J. Biochem. 98, 117–123.PubMedGoogle Scholar
  18. Igarashi, T., Tomihari, N., Ohmori, S., Ueno, K., Kitagawa, H., and Satoh, T. (1986). Comparison of glutathione S-transferases in mouse, guinea pig, rabbit and hamster liver cytosol to those in rat liver. Biochem. International 13, 641–648.Google Scholar
  19. Jakoby, W.B., Habig, W.H., Keen, J.N., Ketley, J.N. and Pabst, M.J. (1976). Glutathione S-transferases: catalytical aspects. In: Glutathione: Metabolism and Function, Arias, I.M. and Jakoby, W.B. (eds): New York, Raven Press, pp. 189–201.Google Scholar
  20. Jakoby, W.B., Ketterer, B. and Mannervik, B. (1984). Glutathione transferases: nomenclature. Biochem. Pharmacol. 33, 2539–2540.CrossRefPubMedGoogle Scholar
  21. Jensson, H., Guthenberg, C., alin, P., and Mannervik, B. (1986). Rat glutathione transferase 8–8, an enzyme efficiently detoxifying 4-hydroxyalk-2-enals. FEBS Lett. 203, 207–209.CrossRefPubMedGoogle Scholar
  22. Jernström, B., Martinez, M., Meyer, D.J., and Ketterer, B. (1985). Glutathione conjugation of the carcinogenic and mutagenic electrophile (+)-713,8a-dihydroxy-9a,10a-oxy-7,8,9,10-tetrahydrobenzo(a)pyrene catalyzed by purified rat liver glutathione transerases. Carcinogenesis 6, 85–89.CrossRefPubMedGoogle Scholar
  23. Ketterer, B. (1988). Protective role of glutathione and glutathione transferases in mutagenesis and carcinogenesis. Mutat. Res. 202, 343–361.Google Scholar
  24. Litwack, G., Ketterer, B., and Arias, I.M. (1971). Ligandin: a hepatic protein which binds steroids, bilirubin, carcinogens and a number of organic anions. Nature (London) 234, 466–467.CrossRefGoogle Scholar
  25. Mannervik, B. (1985). The isoenzymes of glutathione transferase. Adv. Enzymol. Rel. Areas Mol. Biol. 57, 357–417.Google Scholar
  26. Mannervik, B., and danielson, U.H. (1988). Glutathione transferases-structure and catalytic activity. CRC Crit. Rev. Biochem. 23, 283–337.CrossRefPubMedGoogle Scholar
  27. Milbert, U. (1986). Ph.D.-Thesis, University of Mainz.Google Scholar
  28. Pickett, C.B., Telakowski-Hopkins, C.A., Ding, G.J., argenbright, L., and Lu, A.Y.H. (1984). Rat liver glutathione S-transferases. Complete nucleotide sequence of a glutathione S-transferase mRNA and the regulation of the Ya, Yb, and Ye mRNA by 3-methylcholanthrene and phenobarbital. J. Biol. Chem. 259, 5182–5188.PubMedGoogle Scholar
  29. Robertson, I.G.C., Guthenberg, C., Mannervik, B. and Jernström, B. (1986). Differences in stereoselectivity and catalytic efficiency of three human glutathione transferases in the conjugation of glutathione with 70,8a-dihydroxy-9a,10a-oxy-7,8,9,10-tetrahydrobenzo(a)pyrene. Cancer Res. 46, 2220–2224.PubMedGoogle Scholar
  30. Robertson, I.G.C., Jensson, H., Mannervik, B. and Jernström, B. (1986). Glutathione transferases in rat lung: the presence of transferase 7–7, highly efficient in the conjugation of glutathione with the carcinogenic (+)-713,8a-dihydroxy-9a,10a-oxy-7,8,9,10-tetrahydrobenzo(a)pyrene. Carcinogenesis 7, 295–299.CrossRefPubMedGoogle Scholar
  31. Robertson, I.G.C. Jernström, B. (1986). The enzymatic conjugation of glutathione with bay-region diol-epoxides of benzo(a)pyrene, benz(a)anthracene and chrysene. Carcinogenesis 7, 1633–1636.CrossRefPubMedGoogle Scholar
  32. Sato, K. (1989). Glutathione transferases as markers of preneoplasia and neoplasia. Adv. Cancer Res. 52, 205–255.CrossRefGoogle Scholar
  33. Sies, H., and Ketterer, B. (1988) (Eds.). Glutathione conjugation: mechanisms and biological significance. Academic Press, New York.Google Scholar
  34. Suguoka, Y., Kano, T., Okuda, A., Sakai, M., Kitagawa, T., and Muramatsu, M. (1985). Cloning and the nucleotide sequence of rat glutathione S-transferase P cDNA. Nucleic Acids Res. 13, 6049–6057.CrossRefPubMedGoogle Scholar
  35. Telakowski-Hopkins, C.A., King, R.G., and Pickett, C.B. (1988). 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.CrossRefPubMedGoogle Scholar
  36. Telakowski-Hopkins, C.A., Rothkopf, G.S., and Pickett, C.B. (1986). Structural analysis of a rat liver glutathione S-transferase Ya gene. Proc. Natl. Acad. Sci. USA 83, 9393–9397.CrossRefGoogle Scholar
  37. Thakker, D.R., Yagi, H., Levin, W., Wood, A.W., Conney, A.H., and Jerina, D.M. (1985). Polycyclic aromatic hydrocarbons: metabolic activation to ultimate carcinogens. In: Bioactivation of Foreign Compounds ( M.W. Anders, Ed.) pp. 177–242. New York, Academic Press.Google Scholar

Copyright information

© Plenum Press, New York 1991

Authors and Affiliations

  • Franz Oesch
    • 1
  • Ingolf Gath
    • 1
  • Takashi Igarashi
    • 1
  • Hansruedi Glatt
    • 1
  • Barbara Oesch-Bartlomowicz
    • 1
  • Helmut Thomas
    • 1
  1. 1.Institute of ToxicologyUniversity of MainzMainzFederal Republic of Germany

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