Metabolism and the “Initiation” of Tumors by Chemicals

  • Charles M. King
Part of the Prostaglandins, Leukotrienes, and Cancer book series (PLAC, volume 2)


This presentation is based on the idea that genomic alterations by carcinogens are crucial to the production of tumors. The objective is to provide insight as to how investigators may wish to approach the identification and characterization of metabolic activation pathways, as well as the clarification of the role of these pathways in the induction of tumors. It is not intended to be an encyclopedic review, but rather a communication that reflects personal experience in the field of aromatic amines and the external influences of the carcinogenesis community. Hopefully, it will serve both as an introduction to the subsequent chapters of this book and as a framework for the investigation of the mechanisms by which other as yet unstudied compounds cause cancer.


Polycyclic Aromatic Hydrocarbon Mammary Gland Aromatic Amine Adduct Formation Hydroxamic Acid 
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. 1.
    Doll R, Peto R: The causes of cancer: quantitative estimates of avoidable risks of cancer in the United States today. J Natl Cancer Inst (66): 1191–1308, 1981.PubMedGoogle Scholar
  2. 2.
    Parkes HG: The epidemiology of aromatic amine cancers. In: CE Searle (ed) Chemical Carcinogens, Monograph No. 173. American Chemical Society, Washington, DC, 1976, pp 462–480.Google Scholar
  3. 3.
    King CM, Wang CY, Lee M-S, Vaught JB, Hirose M, Morton KC: Metabolic activation of aromatic amines and the induction of liver, mammary gland and urinary bladder tumors in the rat. In: Rydstrom J, Montelius J, Bengtsson M (ed) Extrahepatic Drug Metabolism and Chemical Carcinogenesis. Elsevier Science Publishers, Amsterdam, 1983, pp 557–566.Google Scholar
  4. 4.
    Gilden RV, Rice NR: Oncogenes. Carcinogenesis (4): 791–794, 1983.CrossRefGoogle Scholar
  5. 5.
    Sesnowitz-Horn S, Adelberg A: Proflavin treatment of E. Coli generation of frameshift mutants. Cold Spring Harbor Symp Quant Biol (33): 393–402, 1968.PubMedGoogle Scholar
  6. 6.
    Dipple A: Polynuclear aromatic carcinogens. In: Searle CE (ed) Chemical Carcinogens, Monograph No. 173. American Chemical Society, Washington, DC, 1976, pp 245–314.Google Scholar
  7. Environmental Health Perspectives (49): 1–243, 1983.Google Scholar
  8. 8.
    Jerina DM, Lehr R, Schaefer-Ridder M, Yagi H, Karle JM, Thakker DR, Wood AW, Lu AYH, Ryan D, West S, Levin W, Conney AH: Bay-region epoxides of dihydrodiols: A concept explaining the mutagenic and carcinogenic activity of benzo[a]pyrene and benzo[a]anthracene. In: Hiatt HH, Watson JD, Winsten JA (eds) Origins of human cancer. Book B. Mechanisms of Carcinogenesis, Cold Spring Harbor Cenferences on Cell Proliferation, Volume 4, Cold Spring Harbor Laboratory, 1977, pp 639–658.Google Scholar
  9. 9.
    Gulino PM, Pettigrew HM, Grantham FH: N-Nitrosomethlyurea as mammary carcinogen in rats. J Natl Cancer Inst (54): 401–414, 1975.Google Scholar
  10. 10.
    Hicks RM, Wakefield JSTJ: Rapid induction of bladder cancer in rats with N-Methyl-N-nitrosourea, I. Histology. Chem-Biol Interactions (5): 139–152, 1972.CrossRefGoogle Scholar
  11. 11.
    Nelson N: The chioro ethers: occupational carcinogens, A summary of laboratory and epidemiology studies. Ann NY Acad Sci (271): 81, 1976.PubMedCrossRefGoogle Scholar
  12. 12.
    Miller EC: Some current perspectives on chemical carcinogenesis in humans and experimental animals: presidential address. Cancer Res (38), 1479–1496, 1978.PubMedGoogle Scholar
  13. 13.
    Miller EC, Miller JA, Hartman HA: N-hydroxy-2-acetylaminofluorene, a metabolite of 2-acetylaminofluorene with increased carcinogenic activity in the rat. Cancer Res (31): 815–824, 1961.Google Scholar
  14. 14.
    King CM, Phillips B: Enzyme-catalyzed reactions of the carcinogen N-hydroxy-2-fluorenylacetamide with nucleic acid, Science (Wash) (159): 1351–1353, 1968.CrossRefGoogle Scholar
  15. 15.
    Miller EC, Miller JA: The presence and significance of bound aminoazo dyes in the livers of rats fed E-dimethylaminoazobenzene. Cancer Res (7): 468–480, 1947.Google Scholar
  16. 16.
    Baird WM: The use of radioactive Carcinogens to detect DNA modifications. In: Grover PL (ed) Chemical Carcinogens and DNA, Vol. 2. Boca Raton, Florida, CRC Press, 1979, pp 59–83.Google Scholar
  17. 17.
    King CM, Phillips B: N-Hydroxy-2-fluorenylacetamide: reaction of the carcinogen with guanosine, ribonucleic acid, deoxyribonucleic acid, and protein following enzymatic deacetylation or esterification. J Biol Chem (224): 2609–2616, 1969.Google Scholar
  18. 18.
    Poirier MC, True BA, Laishes BA: Determination of 2-acetylaminofluorene adducts by immunoassay. Environmental Health Perspectives (49): 93–99, 1982.CrossRefGoogle Scholar
  19. 19.
    King CM, Kriek E: The differential reactivity of the oxidation products of o-aminophenols towards protein and nucleic acid. Biochim-Biophys Acta (111): 147–153, 1965.PubMedGoogle Scholar
  20. 20.
    King CM, Phillips B: The non-reactivity of 1,2-fluorenoquinone-2-acetamide with DNA and sRNA. Biochem Pharmacol (17): 833–835, 1968.PubMedCrossRefGoogle Scholar
  21. 21.
    DeBaun JR, Miller EC, Miller JA: N-Hydroxy-2-acetylaminofluorene sulfotransferase: its probable role in carcinogenesis and protein-(methion-S-yl) binding in rat liver. Cancer Res (30): 577–595, 1970.PubMedGoogle Scholar
  22. 22.
    Bartsch H, Dworkin M, Miller J A, Miller EC: Electrophilic N-acetoxyaminoarenes derived from carcinogenic N-hydroxy-N-acetylaminoarenes by enzymatic deacetylation arid transacetylation in liver. Biochim Biophys Acta (286): 272–298, 1972.Google Scholar
  23. 23.
    Westra JG, Kriek E, Hittenhausen H: Identification of the persistently bound form of the carcinogen N-acetyl-2-aminofluorene to rat liver DNA in vivo. Chem-Biol Interactions (15): 287–303, 1976.Google Scholar
  24. 24.
    King CM: Mechanism of reaction, tissue distribution and inhibition of arylhydroxamic aid acyltransferase. Cancer Res (34): 1503–1516, 1974.PubMedGoogle Scholar
  25. 25.
    Lee M-S, King CM: New synthesis of N-(guanosin-8-yl)-4-aminobiphenyl and its 5’monophosphâte. Chem-Biol Interactions (34): 239–248, 1981.CrossRefGoogle Scholar
  26. 26.
    King CM, Traub NR, Cardona RA, Howard RB: Comparative adduct formation of 4-aminobiphenyl and 2-aminofluorene derivatives with macromolecules of isolated liver parenchymal cells. Cancer Res (36): 2374–2381, 1976.PubMedGoogle Scholar
  27. 27.
    McQueen CA, Maslansky CJ, Williams GM: Role of the acetylation polymorphism in determining susceptibility of cultured rabbit hepatocytes to DNA damage by aromatic amines. Cancer Res (43): 3120–3123, 1983.Google Scholar
  28. 28.
    Howard PC, Casciano DA, Beland FA, Shaddock JG Jr: The binding of N-hydroxy-2-acetylaminofluorene to DNA and repair of the adducts in primary rat hepatocyte culture. Carcinogenesis (2): 97–102, 1981.PubMedCrossRefGoogle Scholar
  29. 29.
    Staino N, Erickson LC, Smith CL, Marsden E, Thorgeirsson S: Mutagenicity and DNA damage induced by arylamines in the Salmonella/hepatocyte system. Carcinogenesis (4): 161–167, 1983.CrossRefGoogle Scholar
  30. 30.
    Shirai T, King CM: Sulfotransferase and deacetylase in normal and tumor-bearing liver of CD rats: autoradiographic studies with N-hydroxy-2-acetylaminofluorene and N-hydroxy-4-acetylaminobiphenyl in vitro and in vivo. Carcinogenesis (3): 1385–1391, 1982.PubMedCrossRefGoogle Scholar
  31. 31.
    Wang CY, Linsmaier-Bednar EM, Garner CD, Lee M-S: Induction of unscheduled DNA synthesis in primary culture of dog, rat and mouse urothelial cells by arylamine and nitrofuran derivatives. Cancer Res (42): 3974–3977, 1982.PubMedGoogle Scholar
  32. 32.
    Wang CY, Garner CD, Lee M-S, Shirai T: 0-esters of N-acylhydroxylamines: toxicity and enhancement of sister-chromatid exchange in Chinese hamster ovary cells. Mutation Res (88): 81–88, 1981.Google Scholar
  33. 33.
    Parke DV: The biochemistry of foreign compounds. Pergamon Press, New York, 1968, pp 34–98.Google Scholar
  34. 34.
    Glowinski IB, Savage L, Lee M-S, King CM: Relationship between nucleic acid adduct formation and deacylation of arylhydroxamic acids. Carcinogenesis (4): 67–75, 1983.PubMedCrossRefGoogle Scholar
  35. 35.
    Irving CC, Russell LT: Synthesis of the o-glucuronide of N-2-fluorenylhydroxylamine: reaction with nucleic acids and with guanosine-5’-monophosphate. Biochemistry (9): 2471–2476, 1970.PubMedCrossRefGoogle Scholar
  36. 36.
    Morton KC, King CM, Vaught JB, Wang CY, Lee M-S, Marnett LJ: Prostaglandin H synthase-catalyzed reaction of carcinogenic arylamines with tRNA and homopolyribonucleotides. Biochem Biophys Res Commun (111): 96–103, 1983.PubMedCrossRefGoogle Scholar
  37. 37.
    Kriek E, Reitsema J: Interaction of the carcinogen N-acetoxy-2-acetylaminofluorene with polyadenylic acid: dependence of reactivity on conformation. Chem-Biol Interactions (3): 397–400, 1971.CrossRefGoogle Scholar
  38. 38.
    Moore PD, Koreeda M: Application of the change in partition coefficients with pH to the structure determination of alkyl-substituted guanosines. Biochem Biophys Res Commun (73): 459–464, 1976.PubMedCrossRefGoogle Scholar
  39. 39.
    Grover PL (ed) Chemical Carcinogens and DNA, Volumes I and II, CRC Press, Boca Raton, Florida, 1979, pp 440.Google Scholar
  40. 40.
    Phillips DH, Sims P: Polycyclic aromatic hydrocarbon metabolites: Their reactions with nucleic acids. In: Grover PL (ed) Chemical Carcinogens and DNA, Volume II, CRC Press, Boca Raton, Florida, 1979, 29–58.Google Scholar
  41. 41.
    Rannug U, Sundvall A, Ramel C: The mutagenic effect of 1,2-dichloroethane on Salmonella typhimuriumI. activation through conjugation with glutathione in vitro.Chem-Biol Interactions (20): 1–16, 1978.CrossRefGoogle Scholar
  42. 42.
    Glowinski IB, Fysh JM, Vaught JB, Weber WW, King CM: Evidence for common genetic control of arylhydroxamic acid N-O-acyltransferase and N-acetyltransferase of rabbit liver. J Biol Chem (255): 7883–7890, 1980.PubMedGoogle Scholar
  43. 43.
    Lotlikar PD, Zaleski K: Ring-and N-hydroxylation of 2-acetylaminofluorene by rat liver reconstituted cytochrome P-450 enzyme system. Biochem J (150): 561–564, 1975.PubMedGoogle Scholar
  44. 44.
    Slaga TJ, Gleason GL, Mills G, Wald LE, Fu PP, Lee HM, Harvey RG: Comparison of the skin tumor-initiating activities of dihydrodiols and diol-epoxides of various polycyclic aromatic hydrocarbons. Cancer Res (40): 1981–1984, 1980.PubMedGoogle Scholar
  45. 45.
    Allaben WT, Weeks CE, Weis CC, Burger GT, King CM: Rat mammary gland carcinogenesis after local injection of N-hydroxy-N-acyl-2-aminofluorenes: relationship to metabolic activation. Carcinogenesis (3): 233–240, 1982.PubMedCrossRefGoogle Scholar
  46. 46.
    King CM, Allaben, WT: Arylhydroxamic acid acyltransferase. In: Jakoby WB (ed) Enzymatic Basis of Detoxication. Academic Press, New York, 1980, pp 187–197.Google Scholar
  47. 47.
    Gaugler BJM, Neumann H-G: The binding of metabolites formed from aminostilbene derivatives to nucleic acids in the liver of rats. Chem-Biol Interactions (24): 355–372, 1979.CrossRefGoogle Scholar
  48. 48.
    Clayson DB, Garner RC: Carcinogenic aromatic amines and related compounds. In: Searle CE (ed) Chemical Carcinogens, Monograph No. 173, American Chemical Society, Washington DC, 1976, pp 366–461.Google Scholar
  49. 49.
    Shirai T, Lee M-S, Wang CY, King, CM: 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): 2450–2456, 1981.PubMedGoogle Scholar
  50. 50.
    Hilbert D, Romen W, Neumann H-G: The role of partial hepatectomy and promoters in the formation of tumors in non-target tissues of trans-4-acetylaminostilbene in rats. Carcinogenesis (4): 1519–1525, 1983.CrossRefGoogle Scholar
  51. 51.
    Mulder GJ, Meerman JHN: Sulfation and glucuronidation as competing pathways in the metabolism of hydroxamic acids: The role of N,O-sulfonation in chemical carcinogenesis of aromatic amines. Environmental Health Perspectives (49): 27–32, 1983.PubMedCrossRefGoogle Scholar
  52. 52.
    Dao TL: Studies on mechanism of carcinogenesis in the mammary gland. Progr Exptl Tumor Res (11): 235–261, 1969.Google Scholar
  53. 53.
    Malejka-Giganti D, Rydell RE, Gutmann HR: Mammary carcinogenesis in the rat by topical application of fluorenylhydroxamic acids and their acetates. Cancer Res (37): 111–117, 1977.PubMedGoogle Scholar
  54. 54.
    Irving CC: Species and tissue variations in the metabolic activation of aromatic amines. In: Griffin AC, Shaw CR (eds) Carcinogens: Identification and Mechanisms of Action, Raven Press, New York, 1979, pp 211–228.Google Scholar
  55. 55.
    Irving CC, Janss DH, Rusell LT: Lack of N-hydroxy-2-acetylaminofluorene sulfotransferase activity in the mammary gland and Zymbal’s gland of the rat. Cancer Res (31): 387–391, 1977.Google Scholar
  56. 56.
    Wirth PJ, Thorgeirsson SS: Mechanism of N-hydroxy-2-acetylaminofluorene mutagenicity in the Salmonellatest system. Role of N,O-acyltransferase and sulfotransferase from rat liver. Mol Pharmacol (19): 337–344, 1981.Google Scholar
  57. 57.
    Weeks CE, Allaben WT, Louie SC, Lazear EJ, King CM: Role of hydroxamic acid acyltransferase in the mutagenicity of N-hydroxy-N-2-fluorenylacetamine in Salmonella typhimurium Cancer Res (38): 613–618, 1978.PubMedGoogle Scholar
  58. 58.
    Shirai T, Fysh JM, Lee M-S, Vaught JB, King CM: 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, 1981.PubMedGoogle Scholar
  59. 59.
    King CM, Traub NR, Lortz ZM, Thissen MR: Metabolic activation of arylhydroxamic acid N-O-acyltransferase of rat mammary gland, Cancer Res (39): 3369–3372, 1979.PubMedGoogle Scholar
  60. 60.
    Allaben WT, Weis CC, Fullerton NF, Beland, FA: Formation and persistance of DNA adducts from the carcinogen N-hydroxy-2-acetylaminofluorene in rat mammary gland in vivo. Carcinogenesis (4): 1067–1070, 1983.PubMedCrossRefGoogle Scholar
  61. 61.
    Irving CC, Wiseman R, Hill JT: Bilary excretion of the o-glucuronide of N-hydroxy-2-acetylaminofluorene by the rat and rabbit. Cancer Res (27): 2309–2317, 1967.PubMedGoogle Scholar

Copyright information

© Martinus Nijhoff Publishing, Boston 1985

Authors and Affiliations

  • Charles M. King

There are no affiliations available

Personalised recommendations