Abstract
In recent years work in our laboratory has identified the principal ultimate electrophilic and carcinogenic metabolites formed in vivo in mouse liver from several classes of chemical carcinogens, especially in relation to DNA adduct and hepatoma formation. These carcinogens comprised several naturally occuring alkenylbenzenes and their proximate carcinogenic l’-hydroxy metabolites (Boberg et al., 1983; Wiseman et al., 1987), the synthetic alkyne, l’-hydroxy-2’,3-’dehydroestragole (Fennell et al., 1985); 4-aminoazobenzene and its proximate carcinogenic metabolite, N-hydroxy-4aminoazobenzene (Delclos et al., 1986), and 2-acetylamino-fluorene (Lai et al., 1985, 1987, 1988). In each of these cases, the ultimate reactive carcinogen leading to DNA adduct formation and hepatoma formation appears to be an electrophilic sulfuric acid ester generated by one or more 3’-phospho-adenosine-5’-phosphosulfate (PAPS)-dependent sulfotransferase activities in the liver cytosol. It appears possible from the work of others that the carcinogenic activity of 2,6-dinitrotoluene (Kedderis et al., 1984; Chism and Rickert, 1989), certain nitrosamine derivatives (Sterzel and Eisenbrand, 1986; Kokkinakis et al., 1986; Kroeger-Koepke et al., 1989), and certain drugs with 13-aminoalcohol moiety such as pronethalol (Bicker and Fischer, 1974) may also involve sulfuric acid ester metabolites. The oncogenic purine derivative, 3-hydroxyxanthine has also been thought to be activated by sulfotransferase activity (Stöhrer et al., 1972; Anderson et al., 1978).
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Preview
Unable to display preview. Download preview PDF.
References
Anderson, L.M., McDonald, J.J., Budinger, J.M., Mountain, I.M. and Brown, G.B. (1978). 3-Hydroxyxanthine: transplacental effects and ontogeny of related sulfate metabolism in rats and mice. J. Natl. Cancer Inst. 61, 1405–1410.
Bicker, U. and Fischer, W. (1974). Enzymatic aziridine synthesis from p-amino-alcohols; a new example of endogenous carcinogen formation. Nature 249, 344–345.
Boberg, E.W., Miller, E.C., Miller, J.A., Poland, A. and Liem, A. (1983). Strong evidence from studies with brachymorphic mice and pentachlorophenol that l’- sulfooxysafrole is the major ultimate electrophilic and carcinogenic metabolite of l’-hydroxysafrole in mouse liver. Cancer Res. 43, 5163–5173.
Carlstedt-Duke, J. and Gustafsson, J.-A. (1973). Sexual differences in hepatic sulphurylation of deoxycorticosterone in rats. Eur. J. Biochem. 36, 172–177.
Cavalieri, E.L., Roth, R.W. and Rogan, E.G. (1979). Hydroxylation and conjugation at the benzylic carbon atom: a possible mechanism of carcinogenic activation for some methyl-substituted aromatic hydrocarbons. In Polynuclear Aromatic Hydrocarbons ( P.W. Jones and P. Leber, Eds.), pp. 517–529. Ann Arbor Science, ann Arbor, MI.
Chism, J.P. and Rickert, D.E. (1989). In vitro activation of 2-aminobenzyl alcohol and 2-amino-6-nitrobenzyl alcohol, metabolites of 2-nitrotoluene and 2,6- dinitrotoluene. Chem. Res. Toxicol. 2, 150–156.
Delclos, K.B., Miller, E.C., Miller, J.A. and Liem, A. (1986). Sulfuric acid esters as major ultimate electrophilic and hepatocarcinogenic metabolites of 4- aminoazobenzene and its N-methyl derivatives in infant male C57BL/6JxC3H/HeJ Fi (B6C3F1) mice. Carcinogenesis, 7, 277–287.
Fennell, T.R., Wiseman, R.W., Miller, J.A. and Miller, E.C. (1985). Major role of hepatic sulfotransferase activity in the metabolic activation, DNA adduct formation and carcinogenicity of l’-hydroxy-2’,3’-dehydroestragole in infant male C57BL/6JxC3H/HeJ Fi mice. Cancer Res. 45, 5310–5320.
Flesher, J.W. and Sydnor, K.L. (1971). Carcinogenicity of derivatives of 7,12- dimethylbenz[a]anthracene. Cancer Res. 31, 1951–1954.
Flesher, J.W. and Sydnor, K.L. (1973). Possible role of 6-hydroxymethylbenzo[a]pyrene as a proximate carcinogen of benzo[a]pyrene and 6-methylbenzo[alpyrene. Int. J. Cancer 11, 433–437.
Henschler, R., Seidel, A. and Glatt, H.R. (1989a). Phase-II-metabolite genotoxicity of polycyclic aromatic hydrocarbons: a chloromethyl derivative as a mutagenic intermediate from a benzylic sulfate ester. Naunyn-Schmiedeberg’s Arch. Pharmacol. 339 (Suppl.), 26.
Henschler, R., Pauly, K., Godtel, U., Seidel, A., Oesch, F. and Glatt, H.R. (1989b). The mutagenicity of sulphate esters in Salmonella typhimurium is strongly affected by the ions present in the exposure medium. Mutagenesis 4, 309 (GUM abstracts).
Iwasaki, K., Shiraga, T., Tada, K., Noda, K. and Noguchi, H. (1986). Age-and sex-related changes in amine sulphoconjugation in Sprague-Dawley strain rats. Comparison with phenol and alcohol sulphoconjugations. Xenobiotica 16, 717723.
Kedderis, G.L., Dyroff, M.C. and Rickert, D.E. (1984). Hepatic macromolecular covalent binding of the hepatocarcinogen 2,6-dinitrotoluene and its 2,4-isomer in vivo: modulation by the sulfotransferase inhibitors pentachlorophenol and 2,6dichloro-4-nitrophenol. Carcinogenesis 5, 1199–1204.
Kokkinakis, D.M., Hollenberg, P.F. and Scarpelli, D.G. (1986). The role of hepatic sulfotransferases in the activation of ß-hydroxynitrosamines to potentially mutagenie agents. Proc. Am. Assoc. Cancer Res. 30, 167.
Lai, C.-C., Miller, J.A., Miller, E.C. and Liem, A. (1985). N-Sulfooxy-2-aminofluorene is the major ultimate electrophilic and carcinogenic metabolite of N-hydroxy-acetylaminofluorene in the livers of infant male C57BL/6JxC3H/HeJ Fi (B6C3F1) mice. Carcinogenesis 6, 1037–1045.
Lai, C.-C., Miller, E.C., Miller, J.A. and Liem, A. (1987). Initiation of hepatocarcinogenesis in infant male B6C3F1 mice by N-hydroxy-2-aminofluorene or Nhydroxy-2-acetylaminofluorene depends primarily on metabolism to N-sulfooxy2-aminofluorene and formation of DNA-(deoxyguanosine-8-yl)-2-aminofluorene adducts. Carcinogenesis 8, 471–478.
Lai, C.-C., Miller, E.C., Miller, J.A. and Liem, A. (1988). the essential role of microsomal deacetylase activity in the metabolic activation, DNA(deoxyguanosine-8-yl)-2-aminofluorene adduct formation and initiation of liver tumors by N-hydroxy-2-acetylaminofluorene in the livers of infant male B6C3F1 mice. Carcinogenesis 9, 1295–1302.
Lyon, E.S. and Jakoby, W.B. (1980). The identity of alcohol sulfotransferase with hydroxysteroid sulfotransferases. Arch. biochem. biophys. 202, 474–481.
Mulder, G.J. and Scholtens, E. (1977). Phenol sulfotransferase and uridine diphosphate glucuronyltransferase from rat liver in vivo and in vitro. 2,6-dichloro-4nitrophenol as a selective inhibitor of sulphation. Biochem. J. 165, 553–559.
Okuda, H., Hiratsuka, A., Nojima, H. and Watabe, T. (1986). A hydroxymethyl sulphate ester as an active metabolite of the carcinogen, 5-hydroxymethylchrycene. Biochem. Pharmacol. 35, 535–538.
Okuda, H., Nojima, H., Watanabe, N., Miwa, K. and Watabe, T. (1988). Activation of the carcinogen, 5-hydroxymethylchrycene, to the mutagenic sulphate ester by mouse skin sulphotransferase. Biochem. Pharmacol. 37, 970–973.
Okuda, H., Nojima, H., Watanabe, N. and Watabe, T. (1989). Sulphotransferasemediated activation of the carcinogen 5-hydroxymethyl-chrycene. Species and sex differences in tissue distribution of the enzyme activity and a possible participation of hydroxysteroid sulphotransferases. Biochem. Pharmacol. 38, 3003–3009.
Singer, S.S. and Sylvester, S. (1976). Enzymatic sulfation of steroids II. The control of the hepatic cortisol sulfotransferase activity and of the individual hepatic steroid sulfotransferases of rats by goands and gonadal hormones. Endocrinology, 99, 1346–1352.
Singer, S.S. (1985). Preparation and characterization of the different kinds of sulfotransferases. In Biochemical Pharmacology and Toxicology ( D. Zakim Ed.), Vol. I, pp. 95–159. Academic Press, New York.
Sterzel, W. and Eisenbrand, G. (1986). N-Nitrosodiethanolamine is activated in the rat to an ultimate genotoxic metabolite by sulfotransferase. J. Cancer Res. Clin. Oncol. 111, 20–24.
Stohrer, G., Corbin, E. and Brown, G.B. (1972). Enzymatic activation of the oncogen 3-hydroxyxanthine. Cancer Res. 32, 637–642.
Surh, Y.-J., Lai, C.-C., Miller, J.A. and Miller, E.C. (1987). Hepatic DNA and RNA adduct formation from the carcinogen 7-hydroxymethy1–1 2- methylbenz[a]anthraeene and its electrophilic sulfuric acid ester metabolite in preweanling rats and mice. Biochem. Biophys. Res. Commun. 144, 576–582.
Surh, Y.-J., Liem, A., Miller, E.C. and Miller, J.A. (1989). Metabolic activation of the carcinogen 6-hydroxymethylbenzo[a]pyrene: formation of an electrophilic sulfuric acid ester and benzylic DNA adducts in rat liver in vivo and in reactions in vitro. Carcinogenesis 10, 1519–1528.
Watabe, T., Ishizuka, T., Isobe, M. and Ozawa, N. (1982). A 7-hydroxymethyl sulfate ester as an active metabolite of 7,12-dimethylbenz[a]anthracene. Science 215, 403–405.
Watabe, T., Hiratsuka, A., Ogura, K. and Endoh, K. (1985). A reactive hydroxymethyl sulfate ester formed regioselectively from the carcinogen, 7,12- dihydroxymethylbenz[a]anthracene, by rat liver sulfotransferase. Biochem. Biophys. Res. Commun. 131, 694–699.
Watabe, T., Hakamata, Y., Hiratsuka, A. and Ogura, K. (1986). A 7-hydroxymethyl sulphate ester as an active metabolite of the carcinogen, 7- hydroxymethylbenz[a]anthracene. Carcinogenesis 7, 207–214.
Watabe, T., Hiratsuka, A. and Ogura, K. (1987). Sulphotransferase-mediated covalent binding of the carcinogen 7,12-dihydroxymethylbenz[a]anthracene to calf thymus DNA and its inhibition by glutathione transferase. Carcinogenesis 8, 445–453.
Watabe, T., Ogura, K. Okuda, H. and Hiraszuka, A. (1989). Hydroxymethyl sulfate esters as reactive metabolites of the carcinogens, 7-methyl-and 7,12- dihydroxymethylbenzfalanthracenes and 5-methylchrycene. In Xenobiotic Metabolism and Disposition (Proc. 2nd Int. ISSX Meeting) ( R. Kato, R.W. Estabrook and M.N. Cayen, Eds.) pp. 393–400. Taylor and Francis, London.
Wiseman, R.W., Miller, E.C., Miller, J.A. and Liem, A. (1987). Structure-activity studies of the hepatocarcinogenicities of alkenylbenzene derivatives related to estragole and safrole on administration to preweanling male C57BL/6JxC3H/HeJ Fi mice. Cancer Res. 47, 2275–2283.
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 1991 Plenum Press, New York
About this chapter
Cite this chapter
Miller, J.A., Surh, YJ., Liem, A., Miller, E.C. (1991). Electrophilic Sulfuric Acid Ester Metabolites of Hydroxy-Methyl Aromatic Hydrocarbons as Precursors of Hepatic Benzylic DNA Adducts in Vivo. In: Witmer, C.M., Snyder, R.R., Jollow, D.J., Kalf, G.F., Kocsis, J.J., Sipes, I.G. (eds) Biological Reactive Intermediates IV. Advances in Experimental Medicine and Biology, vol 283. Springer, Boston, MA. https://doi.org/10.1007/978-1-4684-5877-0_71
Download citation
DOI: https://doi.org/10.1007/978-1-4684-5877-0_71
Publisher Name: Springer, Boston, MA
Print ISBN: 978-1-4684-5879-4
Online ISBN: 978-1-4684-5877-0
eBook Packages: Springer Book Archive