Skip to main content

N-Substituted Aromatic Compounds

  • Chapter
Chemical Carcinogenesis

Part of the book series: NATO Advanced Study Institutes Series ((NSSA,volume 52))

Abstract

Aromatic compounds that have nitrogen atoms attached to their ring carbons have a potential for eliciting a variety of adverse cytotoxic, mutagenic and carcinogenic responses. The actual biological effects produced by these agents are dependent on their structure, the ability of the host organism to metabolize the compound and the response of the organism to the metabolites that are generated. Although this group of compounds is most often referred to as aromatic amines, the term N-substituted aromatic compounds is more appropriate since it is sufficiently broad to include both nitrocompounds that may be converted metabolically to aromatic amines, as well as metabolites of amines, e.g. hydroxamates, amides and nitroso derivatives, that have quite different chemical properties. This report is intended to provide insight into the carcinogenic potential of these compounds and the mechanisms by which they are believed to effect this activity.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 39.99
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 54.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  • Bartsch, H. and Hecker, E., 1971, On the metabolic activation of N-hydroxy-N-2-acetylaminoflourene. III. Oxidation with horseradish peroxidase to yield 2-nitrosofluorene and N-acetoxy-N-2-acetylaminofluorene, Biochim. Biophys. Acta., 237: 567–578.

    Article  CAS  Google Scholar 

  • Bartsch, H., Dworkin, M., Miller, J.A., and Miller, E.C., 1972, Electrophilic N-acetoxyaminoarenes derived from carcinogenic N-hydroxy-N-acetylaminoarenes by enzymatic deacetylation and transacetylation in liver, Biochim. Biophys. Acta., 286: 272–298.

    Article  PubMed  CAS  Google Scholar 

  • Bartsch, H., Dworkin, C., Miller, E.C., and Miller, J.A., 1973, Formation of electrophilic N-acetoxyarylamines in cytosols from rat mammary gland and other tissues by transacetylation from the carcinogen N-hydroxy-2-acetylaminobiphenyl, Biochim. Biophys. Acta., 304: 42–55.

    Article  PubMed  CAS  Google Scholar 

  • Bengtsson, U., Johansson, S., and Angervall, L., 1978, Malignancies of the urinary tract and their relation to analgesic abuse, Kidney Internatl., 13: 107–113.

    Article  CAS  Google Scholar 

  • Bhanot, 0.S., Khan, S.A., and Chambers, R.W, 1979, A new system for studying molecular mechanisms of mutation by carcinogens, J. Biol. Chem., 254: 12684–12693.

    Google Scholar 

  • Cardona, R.A. and King, C.M., 1976, Activation of the 0-glucuronide of the carcinogen N-hydroxy-2-fluorenylacetamide by enzymatic deacetylation in vitro: formation of fluorenylamine–tRNA adducts, Biochem. Pharmacol., 25: 1051–1056.

    Article  PubMed  CAS  Google Scholar 

  • Clayson, D.B., and Garner, R.C., 1976, Carcinogenic aromatic amines and related compounds, in: “Chemical Carcinogens,” C.E. Searle, ed., American Chemical Society, Washington, D.C

    Google Scholar 

  • Claxton, L. and Husingh, J., 1980, Characterization of the mutagens associated with diesel particle emissions, 11th Annual Meeting Environmental Mutagen Society, March 16–19, p. 54.

    Google Scholar 

  • Coogan, P.S., H.T. Maganini, J.J. Newton, Jr., and G.M. Hass, 1978, Progesterone inhibition of 2-AAF induction of urogenital tumors in rabbits, Lab. Investigations, 38: 339.

    Google Scholar 

  • Cramer, J.W., Miller, J.A., and Miller, E.C., 1960, N-Hydroxylation: a new metabolic reaction observed in the rat with the carcinogen 2-acetylaminofluorene, J. Biol. Chem., 235: 885–888.

    PubMed  CAS  Google Scholar 

  • DeBaun, J.R., Miller, E.C., and Miller, J.A., 1970, N-Hydroxy-2-acetylaminofluorene sulfotransferase: its probable role in carcinogenesis and in protein-(methionS-yl) binding in rat liver, Cancer Res., 30: 577–595.

    Google Scholar 

  • Epler, J.L., Rao, T.K., and Larimer, F.W., 1980, Isolation and identification of mutagenic polycyclic aromatic amines in synthetic crude oils. 11th Annual Meeting, Environmental Mutagen Society, March 16–19, p. 54.

    Google Scholar 

  • Glowinski, I.B., Weber, W.W., Fysh, J.M., Vaught, J.B., and King, C.M., 1980, Evidence that arylhydroxamic acid N,0-acyltransferase and the genetically polymorphic N-acetyltransferase are properties of the same enzyme in rabbit liver, J. Biol. Chem., 255: 7883–7890.

    PubMed  CAS  Google Scholar 

  • Glowinski, I.B., Savage, L., King, C.M., 1981, Relationship between metabolic activation and deacylation of arylhydroxamic acids by liver microsomes of several species, Proc. Am. Can Res., 22: 102.

    Google Scholar 

  • Gutmann, H.R., Malejka-Giganti, D., Barry, E.J., and Rydell, R.E, 1972, On the correlation between the hepatocarcinogenicity of the carcinogen, N-2-fluorenylacetamide, and its metabolic activation by the rat, Cancer Res., 31: 1554–1561.

    Google Scholar 

  • Hoffman, D. and Wynder, E.L., 1976, Environmental respiratory carcinogenesis, in: “Chemical Carcinogens, ACS Monograph 173,” C.E. Searle, ed., American Chemical Society, Washington, D.C.

    Google Scholar 

  • Howard, P.C., Casciano, D.A., Beland, F.A., and Shaddock, J.G., Jr., 1981, The binding of N-hydroxy-2-acetylaminofluorene to DNA and repair of the adducts in primary rat hepatocyte cultures, Carcinogenesis., 2: 97–102.

    Article  PubMed  CAS  Google Scholar 

  • Irving, C.C., 1966, Enzymatic deacetylation of N-hydroxy-2acetylaminofluorene by liver microsomes, Cancer Res., 26: 1390–1396.

    PubMed  CAS  Google Scholar 

  • Irving, C.C., 1979, Species and tissue variations in the metabolic activation of aromatic amines, in: “Carcinogens: Identification and Mechanisms of Action,” Griffin, A.C. and Shaw, C.R., eds., Raven Press, New York.

    Google Scholar 

  • Irving, C.C., Janss, D.H., and Russell, L.T., 1971, Lack of N-hydroxy-2-acetylaminofluorene sulfotransferase activity in the mammary gland and Zymbal’s gland of the rat, Cancer Res., 31: 387–391.

    PubMed  CAS  Google Scholar 

  • Irving, C..C., Wiseman, R., Jr., and Hill, J.T., 1967a, Biliary excretion of the 0–glucuronide of N–hydroxy2–acetylaminofluorene by the rat and rabbit, Can Res., 27–2309–2317.

    Google Scholar 

  • Jarvinen, M., Santti, R.S.S., Hopsu-Havu, V.K., 1979 Partial purification and characterization of two enzymes from guinea pig liver microsomes that hydrolyze carcinogenic amides, 2-acetylaminofluorene and N-hydroxy-2-acetylaminofluorene, Biochem. Pharm., 20: 2971–2982.

    Google Scholar 

  • Kadlubar, F.F., Unruh, L.E., Beland, F.A., Straub, K.M., and Evans, F.A., 1980, In vitro reaction of the carcinogen, N-hydroxy-2-naphthyamine, with DNA at the C-8 and N2 atoms of guanine and at the N6atom of adenine, Carcinogenesis, 1: 139–150.

    Article  PubMed  CAS  Google Scholar 

  • King, C.M., Allaben, W.T., 1980, Arylhydroxamic acid acyltransferase, in: “Enzymatic Basis of Detoxication, Vol. II,” W. Jakoby, ed., Academic Press, Inc.

    Google Scholar 

  • King, C.M., and Kriek, E., 1965, The differential reactivity of the oxidation products of o-aminophenols towards protein and nucleic acid. Biochim. Biophys. Acta., 111: 147–153.

    Article  PubMed  CAS  Google Scholar 

  • King, C.M., and Phillips, B. 1968, Enzyme-catalyzed reactions of the carcinogen N-hydroxy-2-fluorenylacetamide with nucleic acid. Science, 159: 1351–1353.

    Article  PubMed  CAS  Google Scholar 

  • King, C.M., and Phillips, B., 1969, N-Hydroxy-2-fluorenylacetamide. Reaction of carcinogen with guanosine, ribonucleic acid, deoxyribonucleic acid, and protein following enzymatic deacetylation or esterification, J. Biol. Chem., 244.

    Google Scholar 

  • King, C.M., Traub, N.R., Cardona, R.A., and Howard, R.B., 1976, Comparative adduct formation of 4-aminobiphenyl and 2-aminofluorene derivatives with macromolecules of isolated liver parenchymal cells, Can. Res., 36: 2374–2381.

    CAS  Google Scholar 

  • King, C.M., Traub, N.R., Lortz, Z.M.,and Thissen, M.R., 1979, Metabolic activation of arylhydroxamic acids by N-O-acyltransferase of rat mammary gland, Can Res., 3369–3372.

    Google Scholar 

  • Kosuge, T., Tsuji, K., Wakabayashi, K., Okamoto, T., Shudo, K., Iitaka, Y., Itai, A., Sugimura, T., Kawachi, T., Nagao, M., Yahagi, T., and Seino, Y., 1978, Isolation and structural studies of mutagenic principles in amino acid pyrolysates, Chem. Pharm. Bull., 26: 611–619.

    Article  PubMed  CAS  Google Scholar 

  • Kriek, E., 1965 On the interaction of N-2-fluorenylhydroxylamine with nucleic acids in vitro. Biochem. Biophys. Res. Commun., 20: 793–799.

    Google Scholar 

  • Kriek, E., Miller, J.A., Juhl, U., and Miller, E.C., 1967, 8-(N-2-Fluorenylacetamido)guanosine, an arylamidation reaction product of guanosine and the carcinogen N-acetoxy-N-2-fluorenylacetamide in neutral solution, Biochemistry, 6: 177.

    Google Scholar 

  • Kriek, E., and Westra, J.G., 1979, Metabolic activation of aromatic amines and amides and interactions with nucleic acids, in: “Chemical Carcinogens and DNA, Vol. II,” Grover, P.L., ed., CRC Press, Inc., Boca Raton, FA.

    Google Scholar 

  • Lee, M.S., and King, C.M., 1981, New syntheses of N-(guanosin-8-yl)-4-aminobiphenyl and its 5’-monophosphate, Chem. Biol. Interactions, 34: 239–248.

    Article  CAS  Google Scholar 

  • Lofroth, G., 1978, Mutagenicity assay of combustion emissions, Chemosphere, 7: 791–798.

    Article  CAS  Google Scholar 

  • Maher, V.M., Miller, E.C., Miller, J.A., and Szybalski, W., 1968, Mutations and decreases in density of transforming DNA produced by derivatives of the carcinogens 2-acetylaminofluorene and N-methyl-4-aminoazobenzene, Mol. Pharm, 4: 411–426.

    CAS  Google Scholar 

  • Malejka-Giganti, D., and Gutmann, H.R., 1975, N-Hydroxy-2fluorenylacetamide, an active intermediate of the mammary carcinogen N-hydroxy-2-fluorenylbenzenesulfonamide (38980), Proc. Soc. Expl. Biol. Med., 150: 92–97.

    CAS  Google Scholar 

  • Mermelstein, R., Kariazides, D.K., Butler, M., McCoy, E.C., and Rosenkranz, H.S., 1981, The extraordinary mutagenicity of nitropyrenes in bacteria, Mutation Res, 89: 187–196.

    Article  PubMed  CAS  Google Scholar 

  • Miller, E.C., 1978, Some current perspectives on chemical carcinogenesis in humans and experimental animals: presidential address, Cancer Res., 38: 1479–1496.

    PubMed  CAS  Google Scholar 

  • Miller, E.C., Miller, J.A.., and Hartman, H.A., 1961, N-hydroxy-2-acetylaminofluorene: A metabolite of 2-acetylaminfluorene with increased carcinogenic activity in the rat, Cancer Res., 31: 815–824.

    Google Scholar 

  • Moore, P., and Strauss, B.S., 1979, Sites of inhibition of in vitro DNA synthesis in carcinogen-and UV-treated clo X174 DNA, Nature, 278: 664–666.

    Article  PubMed  CAS  Google Scholar 

  • Morton, K.C., Wang, C.Y., Garner, C.D., and Shirai, T., 1981, Carcinogenicity of benzidine, N,N’-diacetylbenzidine, and N-hydroxy-N-N’-diacetylbenzidine for female CD rats, Carcinogenesis, 2: 747–752.

    Article  PubMed  CAS  Google Scholar 

  • National Cancer Institute, 1978a Bioassay of aniline hydrochloride for possible carcinogenicity, CAS No. 142–04–1, NIC–CG–TR–130.

    Google Scholar 

  • National Cancer Institute, 1978b Bioassay of o–Anisidine hydrochloride for possible carcinogenicity, CAS NO. 134–29–0, NCI–CG–TR–89.

    Google Scholar 

  • Neumann, H.G., 1980, On the significance of metabolic activation and binding to nucleic acids of aminostilbene derivatives in vivo, Natl. Cancer Inst. Monogr., in press.

    Google Scholar 

  • Parkes, H.G., 1976, “The epidemiology of the aromatic amine cancers in: Chemical carcinogens, C.E. Searle, ed., Am. Chem. Soc., Washington, D.C.

    Google Scholar 

  • Pitts, J.A., Jr., Van Cauwenberghe, K.S., Grosjean, D., Schmid, J.P., Fitz, D.R., Belser, W.L., Jr., Knudson, G.B., and Hynds, P.M., 1978, Atmospheric reactions of polycyclic aromatic hydrocarbons: facile formation of mutagenic nitro derivatives, Science, 202: 515–519.

    Article  PubMed  Google Scholar 

  • Scribner, D.L., and McCloskey, J.A., 1978, Deamination of 1-methylcytosine by the carcinogen N-acetoxy-4-acetamido stilbene: Implications for hydrocarbon carcinogenesis, J. of Organic Chem, 43: 2085.

    Article  CAS  Google Scholar 

  • Shirai, T., Fysh, J.M., Lee, M.S., Vaught, J.B.,and King, C.M., 1981a, N-hydroxy-N-acylarylamines: relationship of metabolic activation to biological response in the liver and mammary gland of the female CD rat, Cancer Res: 41: 4346–4353.

    CAS  Google Scholar 

  • Shirai, T., and King, C.M., 1981b, Relationship of H-thymidine incorporation to the metabolic activation of arylhydroxamic acids by rat hepatocytes, Proc. Am Assoc. Can Res: 22: 99.

    Google Scholar 

  • Shirai, T., Lee, M.S., Wang, C.Y., King, C.M., 1981c, Effects of partial hepatectomy and dietary phenobarbital on liver and mammary tumorigenesis by two N-hydroxy-N-acylaminobiphenyls in female CD rats, Cancer Res., 41: 2350–2456.

    Google Scholar 

  • Thorgeirsson, S.S., Wirth, P.J., Nelson, W.L., and Lambert, G.H., 1977, Genetic regulation of metabolism and mutagenicity of 2-acetylaminofluorene and related compounds in mice, in: “Origins of Human Cancer,”Hiatt, Watson, Winsten, eds., Cold Spring Harbor, NY.

    Google Scholar 

  • Vaught, J.B., Lee, M.S., Shayman, M.A., Thissen, M.R., and King, C.M, 1981, Arylhydroxylamine-induced ribonucleic acid chain cleavage and chromatographic analysis of arylamine ribonucleic acid adducts, Chem. Biol Interactions, 34: 109–124.

    Article  CAS  Google Scholar 

  • Wang, C.Y., Lee, M.S., King, C.M., and Warner, P.O., 1980, Evidence for nitroaromatics as direct-acting mutagens as airborne particulates, Chemosphere, 9: 83–87.

    Article  CAS  Google Scholar 

  • Weber, W.W., 1973, Acetylation of drugs, in: “Metabolic conjugation and metabolic hydrolysis”, W.H. Fishman, ed., Academic Press, New York.

    Google Scholar 

  • Weeks, C.E., Allaben, W.T., Louie, S.C., Lazear, E.J., and King, C.M., 1978, Role of arylhydroxamic acid acyltransferase in the mutagenicity of N-hydroxy-N-2fluorenylacetamide in Salmonella typhimurium, Cancer Res., 38: 613–618.

    PubMed  CAS  Google Scholar 

  • Weeks, C.E., Allaben, W.T., Tresp, N.M., Louis, S.C., Lazear, E.J., and King, C.M., 1980, Effects of structure of N-acyl-N-2-fluorenylhyroxylamines on arylhydroxamic acid acyltransferase, sulfotransferase and deacylase activities, and on mutations in Salmonella Typhimurium TA 1538, Cancer Res., 40: 1204–1211.

    PubMed  CAS  Google Scholar 

  • Wirth, P.J., and Thorgeirsson, S.S., 1980, Mechanism of N-hydroxy-2-acetylaminofluorene mutagenicity in the Salmonella test system, role of N-O-acyltransferase and sulfotransferase from rat liver, Mol. Pharm: 19: 337–344.

    Google Scholar 

  • Wu, S-C.G., and Straub, K.D., 1976,. Purification and characterization of N-hydroxy-2-acetylaminofluorene sulfotransferase from rat liver, J. Biol. Chem., 251: 6529–6536.

    Google Scholar 

  • Zavon, M.R., Hoegg, R., and Bingham, E., 1973, Benzidine exposure as a cause of bladder tumors, Arch. Environ. Health, 27: 1–7.

    PubMed  CAS  Google Scholar 

  • Zenser, T.V., Mattammal, M.B., Armbrecht, H.J., and Davis, B.B., 1980, Benzidine binding to nucleic acids mediated by the peroxidative activity of prostaglandin endoperoxide synthetase, Can Res., 40: 2839–2845.

    CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 1982 Plenum Press, New York

About this chapter

Cite this chapter

King, C.M. (1982). N-Substituted Aromatic Compounds. In: Nicolini, C. (eds) Chemical Carcinogenesis. NATO Advanced Study Institutes Series, vol 52. Springer, Boston, MA. https://doi.org/10.1007/978-1-4684-4334-9_2

Download citation

  • DOI: https://doi.org/10.1007/978-1-4684-4334-9_2

  • Publisher Name: Springer, Boston, MA

  • Print ISBN: 978-1-4684-4336-3

  • Online ISBN: 978-1-4684-4334-9

  • eBook Packages: Springer Book Archive

Publish with us

Policies and ethics