Roles of Udp-Glucuronosyltransferase in the Inactivation of Benzo(a)Pyrene

  • K. W. Bock
  • B. S. Bock-Hennig
  • W. Lilienblum
  • H. Pfeil
  • R. F. Volp
Part of the Advances in Experimental Medicine and Biology book series (AEMB)


It has become increasingly clear that the accumulation of reactive intermediates in cells depends upon a delicate balance between activating and detoxifying enzymes and upon numerous other pharmacokinetic factors. The importance of conjugating enzymes such as UDP-gIucuronosyltransferase (GT), which uses nucleophilic substrates instead of reactive electrophiles, is only recently beginning to be recognized in toxicological studies. It has become obvious that nucleophilic intermediate metabolites of aromatic hydrocarbons are often further metabolized to ultimate carcinogens (Sims et al., 1974; Levin et al., 1978). Moreover, glucuronides may be stable transport forms of toxic intermediates which may be reactivated at a site distant from their formation (Kadlubar et al., 1977; Kinoshita and Gelboin, 1978; Mulder et al., 1978).


Liver Microsome Enzyme Form Ames Test Apparent Homogeneity Revertant Coloni 
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. Ames, B. N., McCann, J., and Yamasaki, E., 1975, Methods for detecting carcinogens and mutagens with the Salmonella/mammalian-microsome mutagenicity test, Mutation Res., 31: 347.PubMedCrossRefGoogle Scholar
  2. Basler, A., and Röhrborn, G., 1976, Chromosome aberrations in oocytes of NMRI mice and bone marrow cells of Chinese hamsters induced with 3,4-benzpyrene, Mutation Res., 38: 327PubMedCrossRefGoogle Scholar
  3. Bock, K. W., Fröhling, W., Remmer, H., and Rexer, B., 1973, Effects of phenobarbital and 3-methylcholanthrene on substrate specificity of rat liver microsomal UDP-glucuronyltransferase, Biochim. Biophys. Acta, 327: 46.PubMedCrossRefGoogle Scholar
  4. Bock, K. W., Van Ackeren, G., Lorch, F., and Birke, F. W „ 1976, Metabolism of naphthalene to naphthalene dihydrodiol glucuronide in isolated hepatocytes and in liver microsomes, Biochem. Pharmacol., 25: 2351.Google Scholar
  5. Bock, K. W., 1978, Increase of liver microsomal benzo(a)- pyrene monooxygenase activity by subsequent glucuronidation, Naunyn-Schmiedeberg’s Arch. Pharmacol., 304: 77.Google Scholar
  6. Bock, K. W., v.Clausbruch, U. C., and Ottenwälder, H., 1978a, UDP-glucuronyltransferase in perfused rat liver and in microsomes: V. Studies with Gunn rats, Biochem. Pharmacol., 27: 369.Google Scholar
  7. Bock, K. W., Kittel, J., and Josting, D., 1978b, Purification of rat liver UDP-glucuronyltransferase. Separation of two enzyme forms with different substrate specificity and differential inducibility, in: “Conjugation Reactions in Drug Biotransformation,” A. Aitio, ed., Elsevier/NorthHolland Biomedical Press, Amsterdam.Google Scholar
  8. Bock, K. W., and Lilienblum, W., 1979, Activation and induction of rat liver microsomal UDP-glucuronyltransferase with 3-hydroxybenzo(a)pyrene and N-hydroxy-2-naphthylamine as substrates, Biochem.Pharmacol., 28: 695.PubMedCrossRefGoogle Scholar
  9. Bock, K. W., Josting, D„ Lilienblum, W., and Pfeil, H., 1979, Purification of rat-liver microsomal UDPglucuronyltransferase, Eur. J. Biochem., 98: 19.Google Scholar
  10. Bock, K. W., v.Clausbruch, U. C., Kaufmann, R., Lilienblum, W., Oesch, F., Pfeil, H., and Platt, K. L., 1980a, Functional heterogeneity of UDP-glucuronyltransferase in rat tissues, Biochem. Pharmacol., 29: 495.Google Scholar
  11. Bock, K. W., Kahl, R., and Lilienblum, W., 1980b, Induction of rat hepatic UDP-glucuronosyltransferases by dietary ethoxyquin, Naunyn-Schmiedeberg’s Arch. Pharmacol., 310: 249.Google Scholar
  12. Burchell, B., 1978, Substrate specificity and properties of uridine diphosphate glucuronyltransferase purified to apparent homogeneity from phenobarbital-treated rat liver, Biochem. J., 173: 749.PubMedGoogle Scholar
  13. Burchell, B., 1980, Isolation and purification of bilirubin UDP-glucuronyl-transferase from rat liver, FEES Letters, 111: 131.CrossRefGoogle Scholar
  14. Burke, M., Vadi, H., Jernström, B., and Orrenius, S., 1977, Metabolism of benzo(a)pyrene with isolated hepatocytes and the formation and degradation of DNA-binding derivatives, J. Biol. Chem., 252:6424Google Scholar
  15. Del Villar, E., Sanchez, E., Autor, A. P., and Tephly, T. R., 1975, Morphine metabolism, III. Solubi-lization and separation of morphine and p-nitrophenol uridine diphosphoglucuronyltransferases, Mol. Pharmacol., 11: 236.Google Scholar
  16. Dutton, G. J., 1975, Control of UDP-glucuronyltransferase activity, Biochem. Pharmacol., 24: 1835.Google Scholar
  17. Dutton, G. J., and Burchell, B., 1977, Newer aspects of glucuronidation, in: “Progress in Drug Metabolism; Vol. 2, J. W. Bridges and L. F. Chasseaud, eds., Wiley, London.Google Scholar
  18. Fahl, W. E., Shen, L. A., and Jefcoate, C, R., 1978, UDP-glucuronosyl transferase and the conjugation of benzo(a)pyrene metabolites to DNA, Biochem. Biophys. Res. Commun., 85: 891.Google Scholar
  19. Gorski, J. P., and Kasper, C. B:, 1977, Purification and properties of microsomal UDP-glucuronosyltransferase from rat liver, J. Biol, Chem., 252: 1336.Google Scholar
  20. Hems, R., Ross, B, D., Berry, M. N., and Krebs, H. A., 1966, Gluconeogenesis in the perfused rat liver, Biochem. J., 101: 284.Google Scholar
  21. Inscoe, J. K., and Axelrod, J., 1960, Some factors affecting glucuronide formation in vitro, J. Pharm. Exp. Ther., 129: 128.Google Scholar
  22. Kadlubar, F. F., Miller, J. A., and Miller, E. C., 1977, Hepatic microsomal N-glucuronidation and nucleic acid binding of N-hydroxy arylamines in relation to urinary bladder carcinogenesis, Cancer Res., 37: 805.Google Scholar
  23. Kinoshita, N., and Gelboin, H. V., 1978, ß-Glucuronidase catalyzed hydrolysis of benzo(a)pyrene-3-glucuronide and binding to DNA, Science, 199: 307.PubMedCrossRefGoogle Scholar
  24. Levin, W., Wood, A. W., Wislocki, P. G., Chang, R. L., Kapitulnik, J., Mah, H. D., Yagi, H., Jerina,D. M., and Conney, A. H., 1978, Mutagenicity and carcinogenicity of benzo(a)pyrene and benzo(a)pyrene derivatives, in: “Polycyclic Hydrocarbons and Cancer; Vol. 1, H. V. Gelboin and P.O.P. Ts’o, eds.,Academic Press, New York.Google Scholar
  25. Lilienblum, W., and Bock, K. W., 1980, Differential induction of rat liver UDP-glucuronosyltransferase, Naunyn-Schmiedeberg’s Arch. Pharmacol., 311: R55.Google Scholar
  26. Lind, C., Vadi, H., and Ernster, L., 1978, Metabolism of benzo(a)pyrene-3,6-quinone and 3-hydroxybenzo(a)pyrene in liver microsomes from 3-methylcholanthrene-treated rats, Arch. Biochem. Biophys., 190: 97.Google Scholar
  27. Lorentzen, R. J., and Ts’o, P.O.P., 1977, Benzo(a)pyrenedione/benzo(a)pyrenediol oxidation-reduction couples and the generation of reactive reduced molecular oxygen, Biochemistry, 16: 1467.PubMedCrossRefGoogle Scholar
  28. Lueders, K. K., and Kuff, E. L., 1967, Spontaneous and detergent activation of a glucuronyltransferase in vitro, Arch. Biochem. Biophys., 120: 198.Google Scholar
  29. Mulder, G. J., Hinson, J. A., and Gillette, J. R., 1978, Conversion of the N-O-glucuronide and N-O-sulfate conjugates of N-hydroxyphenacetin to reactive intermediates, Biochem. Pharmacol., 27: 1641.PubMedCrossRefGoogle Scholar
  30. Nemoto, N., and Gelboin, H. V., 1976, Enzymatic conjugation of benzo(a)pyrene oxides, phenols and dihy-drodiols with UDP-glucuronic acid, Biochem. Pharmacol., 25: 1221.PubMedCrossRefGoogle Scholar
  31. Okey, A. B., Bondy, G. P., Mason, M. E., Kahl, G. F., Eisen, H. J., Guenthner, T. M., and Nebert, D. W., 1979, Regulatory gene product of the Ah locus,J. Biol. Chem., 254: 1 1636.Google Scholar
  32. Omura, T., Siekevitz, P., and Palade, G. E., 1967, Turnover of constituents of the endoplasmic reticulum membrane of rat hepatocytes, J. Biol. Chem., 242: 2389.Google Scholar
  33. Owens, I. S., 1977, Genetic regulation of UDP-glucuronosyltransferase induction by polycyclic aromatic compounds in mice, J. Biol. Chem., 252: 2827.Google Scholar
  34. Owens, I. S., Koteen, G. M., and Legraverend, C., 1979, Mutagenesis of certain benzo(a)pyrene phenols in vitro following further metabolism by mouse liver,Biochem. Pharmacol., 28: 1615.Google Scholar
  35. Poland, A., Glover, E., and Kende, A. S., 1976, Stereo-specific high affinity binding of 2,3,7,8,-tetrachlorodibenzo-p-dioxin by hepatic cytosol, J. Biol. Chem., 251: 4936.PubMedGoogle Scholar
  36. Selkirk, J. K., Croy, R. G., Roller, P. P„ and Gelboin, H. V., 1974, High-pressure liquid chromatographic analysis of benzo(a)pyrene metabolism and cova-lent binding and the mechanism of action of 7,8-benzoflavone and 1,2-epoxy-3,3,3-trichloropropane, Cancer Res., 34: 3474.PubMedGoogle Scholar
  37. Shen, A. L., Fahl, W. E., Wrighton, S, A., and Jefcoate, C. R., 1979, Inhibition of benzo(a)pyrene and benzo(a)pyrene 7,8-dihydrodiol metabolism by benzo(a)pyrene quinones, Cancer Res., 39: 4123.Google Scholar
  38. Sims, P., Grover, P. L., Swaisland, A., Pal, K., and Hewer, A., 1974, Metabolic activation of benzo(a)pyrene proceeds by a diol-epoxide, Nature (London), 252: 326.Google Scholar
  39. Stramentinoli, G., Gazzaniga, A., Della Bella, D., and Remmer, H., 1974, Increase of chloramphenicol glucuronidation in rats treated with phenobarbital, Biochem. Pharmacol., 23: 1181.PubMedCrossRefGoogle Scholar
  40. Tukey, R. H., Billings, R. E., and Tephly, T. R., 1978, Separation of oestrone UDP-glucuronyltransferase and p-nitrophenol UDP-glucuronyltransferase activities, Biochem. J., 171: 659.PubMedGoogle Scholar
  41. Winsnes, A., 1972, Inhibition of hepatic UDP-glucuronosyltransferase by nucleotides, Biochim. Biophys.Acta, 289: 88.PubMedCrossRefGoogle Scholar
  42. Wishart, G. J., 1978a, Demonstration of functional heterogeneity of hepatic uridine diphosphate glucuronosyltransferase activities after administration of 3-methylcholanthrene and Phenobarbital to rats, Biochem, J., 174: 671.Google Scholar
  43. Wishart, G. J., 1978b, Functional heterogeneity of UDP-glucuronosyltransferase as indicated by its differential development and inducibility by glucocorticoids, Biochem. J., 174: 485.PubMedGoogle Scholar
  44. Wishart, G. J., and Campbell, M. T., 1979, Demonstration of two functionally heterogeneous groups within the activities of UDP-glucuronosyltransferase towards a series of 4-alkyl-substituted phenols, Biochem. J., 178: 443.PubMedGoogle Scholar
  45. Zakim,D., and Vessey, D. A., 1976, The effects of lipid protein interactions on the kinetic parameters of microsomal UDP-glucuronyltransferase, in: The Enzymes of Biological Membranes Vol. 2, A. Martonosi, ed., Plenum Publ. Corp., New York.Google Scholar

Copyright information

© Springer Science+Business Media New York 1982

Authors and Affiliations

  • K. W. Bock
    • 1
  • B. S. Bock-Hennig
    • 1
  • W. Lilienblum
    • 1
  • H. Pfeil
    • 1
  • R. F. Volp
    • 1
  1. 1.Dept. of Pharmacology and ToxicologyUniversity of GöttingenGöttingenWest Germany

Personalised recommendations