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Species Differences of Glucuronidation and Sulfation in Relation to Hepatocarcinogenesis

  • Conference paper
Mouse Liver Tumors

Part of the book series: Archives of Toxicology ((TOXICOLOGY,volume 10))

Abstract

The role of glucuronidation and sulfation in the control of proximal and ultimate carcinogens is briefly reviewed. In accordance with the adopted practice of tumor risk assessment, data from two rodent species (rat, mouse) and man have been compared.

  1. (1)

    Sulfate esters have been established as ultimate carcinogens in 2-acetylaminofluorene, safrole and estragole induced hepatocarcinogenesis. In interspecies comparisons the tumor incidence paralleled sulfotransferase activity (Miller and Miller 1981).

  2. (2)

    Glucuronides are often stable transport forms of carcinogens and in this way determine their organ specificity, for example in 2-naphthylamine-induced bladder carcinogenesis and in colon carcinogenesis produced by 2′,3- dimethyl-4-aminobiphenyl.

  3. (3)

    In contrast to sulfotransferase activity certain UDP-glucuronyltransferase activities are differentially inducible by xenobiotics. A 3-methylcholanthrene- inducible phenol-glucuronyltransferase (GT1), present in rat, mouse and man, appears to be part of an adaptive program to detoxify aromatic hydrocarbons.

  4. (4)

    After initiation of hepatocarcinogenesis permanent alterations of these enzymes occur; GT1 is markedly increased whereas sulfotransferase is decreased. Together with changes of other drug metabolizing enzymes these alterations often lead to toxin-resistance of initiated hepatocytes. This phenomenon may facilitate selective growth of initiated hepatocytes and may enhance the probability of multiple hits in their genome.

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References

  • Boberg EW, Miller EC, Miller JA, Poland A, Liem A (1983) Strong evidence from studies with brachymorphic mice and pentachlorophenol that l’-sulfoöxysafrole is the major ultimate electrophilic and carcinogenic metabolite of 1-hydroxysafrole in mouse liver. Cancer Res 43: 5163–5173

    PubMed  CAS  Google Scholar 

  • Bock KW, Fröhling W, Remmer H, Rexer B (1973) Effects of phenobarbital and 3-methylcholanthrene on substrate specificity of rat liver microsomal UDP-glucuronyltransferase. Biochim Biophys Acta 327: 46–56

    PubMed  CAS  Google Scholar 

  • Bock KW, Josting D, Lilienblum W, Pfeil H (1979) Purification of rat liver microsomal UDP-glucuronyltransferase. Eur J Biochem 98: 19–26

    Article  PubMed  CAS  Google Scholar 

  • Bock KW, Bock-Hennig BS, Lilienblum W, Volp RF (1981) Release of mutagenic metabolites of ben- zo(a)pyrene from the perfused rat liver after inhibition of glucuronidation and sulfation by salicyl- amide. Chem-Biol Interactions 36: 167–177

    Article  CAS  Google Scholar 

  • Bock KW, Lilienblum W, Pfeil H (1982 a) Functional heterogeneity of UDP-glucuronosyltransferase activities in C57BL/6 and DBA/2 mice. Biochem Pharmacol 31: 1273–1277

    Google Scholar 

  • Bock KW, Lilienblum W, Pfeil H, Eriksson LC (1982 b) Increased UDP-glucuronyltransferase activity in preneoplastic liver nodules and Morris hepatomas. Cancer Res 42: 3747–3752

    Google Scholar 

  • Bock KW, Lilienblum W, von Bahr C (1984) Studies of UDP-glucuronyltransferase activities in human liver microsomes. Drug Metab Dispos 12: 93–97

    PubMed  CAS  Google Scholar 

  • Boyland E (1959) The biochemical mechanisms of induction of bladder cancer. In: Wolstenhome GEW, O’Connor M (eds) CIBA Foundation Symposium on Carcinogenesis. Churchill, London, pp 218–229

    Google Scholar 

  • Burchell B (1979) Purification of mouse liver UDP-glucuronosyltransferase. Med Biol 57: 265–268

    PubMed  CAS  Google Scholar 

  • Conney AH (1982) Induction of microsomal enzymes by foreign chemicals and carcinogenesis by polycyclic aromatic hydrocarbons. Cancer Res 42: 4875–4917

    PubMed  CAS  Google Scholar 

  • Dutton GJ (1980) Glucuronidation of Drugs and Other Compounds. CRC Press, Boca Raton, Florida

    Google Scholar 

  • Epstein S, Ito N, Merkow L, Farber E (1967) Cellular analysis of liver carcinogenesis. The induction of large hyperplastic nodules in the liver with N-2-fluorenylacetamide or ethionine and some aspects of their morphology and glycogen metabolism. Cancer Res 27: 1702–1711

    PubMed  CAS  Google Scholar 

  • Eriksson LC (1985) Aspects of drug metabolism in hepatocyte nodules in rats. In: Matern S, Bock KW, Gerok W (eds) Advances in Glucuronide Conjugation. MTP Press, Lancaster, pp 295–308

    Google Scholar 

  • Eriksson LC, Blanck A, Bock KW, Mannervik B (1986) Metabolism of xenobiotics in hepatocyte nodules. Toxicologic Pathology, in press

    Google Scholar 

  • Falany CN, Kirkpatrick RB, Tephly TR (1985) Comparison of rat and rabbit liver UDP-glucuronosyltransferase activities. In: Matern S, Bock KW, Gerok W (eds) Advances in Glucuronide Conjugation. MTP Press, Lancaster, pp 41–49

    Google Scholar 

  • Farber E (1984) Cellular biochemistry of the stepwise development of cancer with chemicals. Cancer Res 44: 5463–5474

    PubMed  CAS  Google Scholar 

  • Fischer G, Ullrich D, Bock KW (1985 a) Effects of N-nitrosomorpholine and phenobarbital on UDP- glucuronyltransferase in putative preneoplastic foci of rat liver. Carcinogenesis 6: 605–609

    Google Scholar 

  • Fischer G, Schauer A, Hartmann H, Bock KW (1985 b) Increased UDP-glucuronyltransferase in putative preneoplastic foci of human liver after long-term use of oral contraceptives. Naturwissen-schaften 72: 277–278

    Google Scholar 

  • Hirom PC, Millburn P, Smith RL, Williams RT (1972) Species variations in the threshold molecular-weight factor for the biliary excretion of organic anions. Biochem J 129: 1072–1077

    Google Scholar 

  • Jakoby WB, Sekura RD, Lyon ES, Marcus CJ, Wang JL (1980) Sulfotransferases. In: Jakoby WB (ed) Enzymatic Basis of Detoxication, vol 2. Academic Press, New York London Toronto Sydney San Francisco, pp 199–228

    Google Scholar 

  • Lilienblum W, Bock-Hennig BS, Bock KW (1985) Protection against toxic redox-cycles between ben- zo(a)pyrene-3,6-quinone and its quinol by 3-methylcholanthrene-inducible formation of the quinol mono- and diglucuronide. Mol Pharmacol 27: 451–458

    PubMed  CAS  Google Scholar 

  • Lind C (1985) Formation of benzo(a)pyrene-3,6-quinol mono- and diglucuronides in rat liver microsomes. Arch Biochem Biophys 240: 226–235

    Article  PubMed  CAS  Google Scholar 

  • Lorentzen RJ, Ts’o POP (1977) Benzo(a)pyrenedione/benzo(a)pyrenediol oxidation-reduction couples and the generation of reactive reduced molecular oxygen. Biochem 16: 1467–1473

    Article  CAS  Google Scholar 

  • Mackenzie PI, Gonzalez FJ, Owens IS (1984) Cloning and characterization of DNA complementary to rat liver UDP-glucuronosyltransferase mRNA. J Biol Chem 259: 12153–12158

    PubMed  CAS  Google Scholar 

  • Miller EC, Miller JA (1981) Searches for ultimate chemical carcinogens and their reactions with cellular macromolecules. Cancer 47: 2327–2345

    Article  PubMed  CAS  Google Scholar 

  • Nebert DW, Jensen NM (1979) The Ah locus: genetic regulation of the metabolism of carcinogens, drugs, and other environmental chemicals by cytochrome P-450-mediated monooxygenases. CRC Crit Rev Biochem 6: 401–437

    Article  PubMed  CAS  Google Scholar 

  • Owens IS (1977) Genetic regulation of UDP-glucuronosyltransferase induction by polycyclic aromatic compounds in mice. J-Biol Chem 252: 2827–2833

    PubMed  CAS  Google Scholar 

  • Owens IS, Mackenzie PI (1984) Differential induction and glycosylation of UDP-glucuronosyltransferase. Biochem Soc Transact 12: 54–55

    CAS  Google Scholar 

  • Pfeil H, Bock KW (1983) Electroimmunochemical quantification of UDP-glucuronosyltransferase in rat liver microsomes. Eur J Biochem 131: 619–623

    Article  PubMed  CAS  Google Scholar 

  • Pickett CB, Telakowski-Hopkins CA, Ding GJF, Argenbright L, Lu AYH (1984) Rat liver glutathione S-transferases. J Biol Chem 259: 5182–5188

    PubMed  CAS  Google Scholar 

  • Poland A, Knutson JC (1982) 2,3,7,8-Tetrachlorodibenzo-p-dioxin and related halogenated aromatic hydrocarbons: examination of the mechanism of toxicity. Ann Rev Pharmacol Toxicol 22:517– 554

    Google Scholar 

  • Roy Chowdhury J, Roy Chowdhury N, Novikoff PM, Novikoff AB, Arias IM (1985) UDP-glucuron- yltransferase: problems within a biological ‘family’. In: Matern S, Bock KW, Gerok W (eds) Advances in Glucuronide Conjugation. MTP Press, Lancaster, pp 33–40

    Google Scholar 

  • Schut HAJ, Wirth PF, Thorgeirsson SS (1978) Mutagenic activation of N-hydroxy-2-acetylaminoflu- orene in the salmonella test system: The role of deacetylation by liver and kidney fractions from mouse and rat. Mol Pharmacol 14: 682–692

    Google Scholar 

  • Scragg I, Celier C, Burchell B (1985) Congenital jaundice in rats due to the absence of hepatic bilirubin UDP-glucuronyltransferase enzyme protein. FEBS Lett 183: 37–42

    Article  PubMed  CAS  Google Scholar 

  • Solt D, Farber E (1976) New principle for the analysis of chemical carcinogenesis. Nature 263:701– 703

    Google Scholar 

  • Thompson TB, Watkins JB, Gregus Z, Klaassen CD (1982) Effect of microsomal enzyme inducers on the soluble enzymes of hepatic phase II biotransformation. Toxicol Appl Pharmacol 66: 400–408

    Article  PubMed  CAS  Google Scholar 

  • Weisburger JH (1971) Colon carcinogens: their metabolism and mode of action. Cancer 28: 60–70

    Article  PubMed  CAS  Google Scholar 

  • Weisburger JH, Yamamoto RS, Williams GM, Grantham PH, Matsushima T, Weisburger EK (1972) On the sulfate ester of N-hydroxy-N-2-fluorenylacetamide as a key ultimate hepatocarcinogen in the rat. Cancer Res 32: 491–500

    PubMed  CAS  Google Scholar 

  • Wiltfang J, Blume R, Bock KW (1986) Paracetamol as a test drug to determine glucuronide formation in patients: effects of inducers and of smoking. Naunyn-Schmiedeberg’s Arch Pharmacol 332: R95

    Google Scholar 

  • Wishart GJ (1978) Demonstration of functional heterogeneity of hepatic uridine diphosphate glucuro- nosyltransferase activities after administration of 3-methylcholanthrene and phenobarbital to rats. Biochem J 174: 671–672

    PubMed  CAS  Google Scholar 

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Author information

Authors and Affiliations

  1. Department of Pharmacology and Toxicology, University of Göttingen, D-3400, Göttingen, Germany

    K. W. Bock & G. Schirmer

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  1. K. W. Bock
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  2. G. Schirmer
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Editor information

Editors and Affiliations

  1. Department of Pharmacology and Therapeutics, Trinity College, University of Dublin, Dublin 2, Ireland

    Philip L. Chambers

  2. Institut für Toxikologie und Pharmakologie, der Universität Würzburg, Versbacher Landstraße 9, 8700, Würzburg, Germany

    Dietrich Henschler

  3. Institut für Toxikologie, der Universität Mainz, Obere Zahlbacher Straße 67, 6500, Mainz, Germany

    Franz Oesch

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© 1987 Springer-Verlag

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Bock, K.W., Schirmer, G. (1987). Species Differences of Glucuronidation and Sulfation in Relation to Hepatocarcinogenesis. In: Chambers, P.L., Henschler, D., Oesch, F. (eds) Mouse Liver Tumors. Archives of Toxicology, vol 10. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-71617-1_10

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  • DOI: https://doi.org/10.1007/978-3-642-71617-1_10

  • Publisher Name: Springer, Berlin, Heidelberg

  • Print ISBN: 978-3-540-17124-9

  • Online ISBN: 978-3-642-71617-1

  • eBook Packages: Springer Book Archive

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