Activation of 1-Hydroxymethylpyrene to an Electrophilic and Mutagenic Metabolite by Rat Hepatic Sulfotransferase Activity

  • Young-Joon Surh
  • Judith C. Blomquist
  • James A. Miller
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 283)


Hydroxylation of meso-methyl groups with subsequent formation of reactive benzylic esters bearing a good leaving group (e.g., sulfate, phosphate, acetate, etc.) has been proposed as a possible activation pathway in the DNA binding and carcinogenicity of some methyl-substituted polycyclic aromatic hydrocarbons (Flesher, et al., 1971; Flesher, et al., 1973). The metabolic formation of such reactive esters has recently been reported by Watabe et al. (1982, 1986, 1987; Okuda, H. et al., 1986). Their studies demonstrated the formation of electrophilic and mutagenic sulfuric acid ester metabolites from 7-hydroxymethy1-12-methylbenz[a]anthracene (HMBA) and related aromatic hydrocarbons by rat liver cytosolic sulfotransferase activity (reviewed in ref. 7). Non-enzymatic interaction of these reactive esters with the amino groups of guanine and adenine residues in calf thymus DNA produced the benzylic adducts. More recently we have noted the formation of such benzylic DNA adducts in vivo in the livers of infant rats and mice treated with HMBA, 6- hydroxymethylbenzo[a]pyrene (HMBP), or their electrophilic sulfuric acid esters (Surh, Y.-J. et al., 1987, 1989). The chemically synthesized sulfuric acid ester of 1- hydroxymethylpyrene (HMP) was also found to be highly mutagenic toward Salmonella typhimurium TA98 (Watabe, T. et al., 1982) and this intrinsic mutagenicity increased dramatically in the presence of chloride ion (Henschler, R., et al. 1989). However, the biological formation of such a labile and reactive sulfuric acid ester of HMP has not been reported.


Sulfate Ester Liver Cytosol Hepatic Cytosol Phosphoric Acid Ester Sulfotransferase Activity 
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  1. 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 1’sulfooxysafrole is the major ultimate electrophilic and carcinogenic metabolite of l’-hydroxysafrole in mouse liver. Cancer Res. 43, 5163–5173.PubMedGoogle Scholar
  2. Flesher, J.W. and Sydnor, K.L. (1971). Carcinogenicity of derivatives of 7,12dimethylbenz[a]anthracene. Cancer Res. 31, 1951–1954.PubMedGoogle Scholar
  3. 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[a]pyrene. Int. J. Cancer 11, 433–437.CrossRefPubMedGoogle Scholar
  4. Henschler, R., Seidel, A. and Glatt, H.R. (1989). 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.), R26.Google Scholar
  5. Henschler, R., Pauly, K., Godtel, U., Seidel, a., Oesch, F. and Glatt, H.R. (1989). The mutagenicity of sulfate esters in Salmonella typhimurium is strongly affected by the ions present in the exposure medium. Mutagenesis 4, 309 (GUM abstracts).Google Scholar
  6. 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 Nhydroxy-2-acetylaminofluorene in the livers of infant male C57BL/6J × C3H/HeJF1 (B6C3F1) mice. Carcinogenesis 6, 1037–1045.CrossRefPubMedGoogle Scholar
  7. Okuda, H., Hiratsuka, A., Nojima, H. and Watabe, T (1986). A hydroxymethyl sulfate ester as an active metabolite of the carcinogen, 5-hydroxymethylchrycene. Biochem. Pharmacol. 35, 535–538.CrossRefPubMedGoogle Scholar
  8. Okuda, H. and Watabe, T. (1989). Formation and metabolism of the active metabolite, 9-hydroxymethyl-l0-methylanthracene phosphate, in rat liver. Proc. Jpn. Cancer Assoc. 44, (abstract #158).Google Scholar
  9. Okuda, H., Yoshioka, S. and Watabe, T. (1989). Sulfotransferase-mediated activation of 9-hydroxymethyl-l0-methylanthracene, a major metabolite of the carcinogen 9,10-dimethylanthracene. Mut. Res. 216, 372 (abstract #38).Google Scholar
  10. Rogan, E.G., Cavalieri, E.L. Walker, B.A., Balasubramanian, R., Wislocki, P.G., Roth, R.W. and Saugier, A.K. (1986). Mutagenicity of benzylic acetates, sulfates and bromides of polycyclic aromatic hydrocarbons. Chem. -Biol. Interact. 58, 253–275.CrossRefPubMedGoogle Scholar
  11. Squires, T.G., Schmidt, W.W. and McCandlish, C.S., Jr. (1975). Zinc chloride catalysis in the reaction of thionyl halides with aliphatic alcohols. J. Org. Chem. 40, 134–136.CrossRefGoogle Scholar
  12. Surh, Y.-J., Lai, C.-C., Miller, J.A. and Miller, E.C. (1987). Hepatic DNA and RNA adduct formation from the carcinogen 7-hydroxymethyl-12methylbenz[a]anthracene and its electrophilic sulfuric acid ester metabolite in preweanling rats and mice. Biochem. Biophys. Res. Commun. 144, 576–582.CrossRefPubMedGoogle Scholar
  13. 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.CrossRefPubMedGoogle Scholar
  14. 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.CrossRefPubMedGoogle Scholar
  15. Watabe, T., Hakamata, Y., Hiratsuka, A. and Ogura, K. (1986). A 7-hydroxymethyl sulfate ester as an active metabolite of the carcinogen, 7-hydroxymethylbenz[a]anthracene. Carcinogenesis 7, 207–214.CrossRefPubMedGoogle Scholar
  16. Watabe, T., Hiratsuka, A. and Ogura, K. (1987). Sulfotransferase-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.CrossRefPubMedGoogle Scholar
  17. Watabe, T., Ogura, K., Okuda, H. and Hiratsuka, A. (1989). Hydroxymethyl sulfate esters as reactive metabolites of the carcinogens, 7-methyl-and 7,12- dimethylbenz[a]anthracenes and 5-methylchrycene. In Xenobiotic Metabolism and Disposition ( Kato, R., Estabrook, R.W. and Cayen, M.N. eds.), pp. 393–400, Taylor and Francis, London.Google Scholar

Copyright information

© Plenum Press, New York 1991

Authors and Affiliations

  • Young-Joon Surh
    • 1
  • Judith C. Blomquist
    • 1
  • James A. Miller
    • 1
  1. 1.McArdle Laboratory for Cancer Research & Environmental Toxicology CenterUniversity of Wisconsin Medical SchoolMadisonUSA

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