Skip to main content
SpringerLink
Log in

N-Hydroxy-N-arylacetamides

I. Toxicity of certain polycyclic and monocyclic N-hydroxy-N-arylacetamides in rats

  • Original Investigations
  • Published:
Archives of Toxicology Aims and scope Submit manuscript

Abstract

  1. 1.

    Of the two carcinogenic N-hydroxy-N-arylacetamides tested, N-hydroxy-4-acetylaminobiphenyl was as active as the monocyclic analogs in the oxidation of hemoglobin, whereas N-hydroxy-2-acetylaminofluorene produced less ferrihemoglobin after IP injection into female and male rats.

  2. 2.

    Monocyclic N-hydroxy-N-arylacetamides, such as N-hydroxy-4-chloroacetanilide or N-hydroxyphenacetin, were more toxic than the parent N-arylacetamides, LD50 in mice being 190 mg/kg for N-hydroxy-4-chloroacetanilide vs 755 mg/kg for 4-chloroacetanilide, and 702 mg/kg for N-hydroxyphenacetin versus 1,220 mg/kg for phenacetin. The higher acute toxicities are probably due, at least in part, to the production of more ferrihemoglobin by the N-hydroxy-N-arylacetamides.

  3. 3.

    Chronic toxicity of N-hydroxy-4-chloroacetanilide was tested on 10 male and 10 female Sprague Dawley rats after IP or SC injection of 20 mg (0.11 mmol)/kg twice weekly for 16 weeks into two groups of 10 animals each (five males, five females, total dose: 3.5 mmol/kg). The experiment, which was terminated after 2 years, did not yield any hint that N-hydroxy-4-chloroacetanilide was carcinogenic in the rat.

  4. 4.

    Subchronic toxicity of N-hydroxyphenacetin was tested in two experiments on male and female Sprague Dawley rats after IP or SC injection of 50 or 100 mg (0.26 or 0.51 mmol)/kg. In the first experiment, two groups of 15 rats each (seven males, eight females) were injected either IP or SC with 50 and 100 mg/kg twice weekly for 29 weeks, and in the second experiment groups of 10 males and 10 females were injected SC with 100 mg/kg twice daily on 5 days a week for 12 weeks. The experiments, which were terminated after 29 weeks and 12 weeks treatment, respectively, did not provide evidence for chronic interstitial nephritis or tumor growth in the kidney.

  5. 5.

    N-Hydroxy-N-arylacetamides were found to be inferior to the corresponding arylhydroxylamines in their ferrihemoglobin-forming capabilities in female rats. Large differences in activity of the arylhydroxylamines and no close relation to the number of rings was observed, N-hydroxy-2-acetylaminofluorene being the least active and N-hydroxy-4-acetylaminobiphenyl being as active as the monocyclic compounds, and exceeding all in the duration of its activity. This indicates the differences in the metabolic stability and availability of the actual ferrihemoglobin-forming molecular species.

  6. 6.

    When the blood of rats injected IP with either 50 mg/kg N-hydroxy-4-chloroacetanilide or 8 mg/kg N-hydroxy-4-chloroaniline was analyzed, similar concentrations of 4-chloronitrosobenzene were determined. This indicates that the hydroxamic acid itself is not active, but after N-deacetylation yields the active arylhydroxylamine. 4-Chloroacetanilide also found in the blood of rats injected IP with N-hydroxy-4-chloroacetanilide is a hint that part of the hydroxamic acid was either reduced by hepatic reductases or oxidized by oxyhemoglobin.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

Abbreviations

HbFe2+ :

Ferrohemoglobin

HbFe3+ :

Ferrihemoglobin

NOH-2AAF:

N-hydroxy-2-acetylaminofluorene; C. A. N-9H-fluoren-2-yl-N-hydroxy-acetamide

NOH-4AAB:

N-hydroxy-4-acetylaminobiphenyl; C. A. N-(1,1′-biphenyl)-4-yl-N-hydroxy-acetamide

NOH-4ClAA:

N-hydroxy-4-chloroacetanilide; C. A. N-(4-chlorophenyl)-N-hydroxy-acetamide

NOH-4EAA:

N-hydroxy-4-ethoxyacetanilide, N-hydroxyphenaccetin; C.A. N-(4-ethoxyphenyl)-N-hydroxy-acetamide

2-AAF:

2-acetylaminofluorene; C. A. N-9H-fluoren-2-yl-acetamide

4-AAB:

4-acetylaminobiphenyl; C. A. N-(1,1′-biphenyl)-4-yl-acetamide

4-ClAA:

4-chloroacetanilide; C. A. N-(4-chlorophenyl)-acetamide

4-EAA:

4-ethoxyacetanilide, phenacetin; C. A. N-(4-ethoxyphenyl)-acetamide

NOH-2AF:

N-hydroxy-2-aminofluorene; C. A. N-hydroxy-9H-fluorene-2-amine

NOH-4AB:

N-hydroxy-4-aminobiphenyl; C. A. N-hydroxy(1,1′-biphenyl)-4-amine

NOH-4ClA:

N-hydroxy-4-chloroaniline; C. A. N-hydroxy-4-chlorobenzenamine

NOH-4EA:

N-hydroxy-4-ethoxyaniline; C. A. N-hydroxy-4-ethoxybenzenamine

NOB:

nitrosobenzene

NO-4ClB:

4-chloronitrosobenzene

NO2-4ClB:

4-chloronitrobenzene

References

  • Bartsch H, Malaveille C, Stich HF, Miller EC, Miller JA (1977) Comparative electrophilicity, mutagenicity, DNA repair induction activity, and carcinogenicity of some N- and O-Acyl derivatives of N-hydroxy-2-aminofluorene. Cancer Res 37: 1461–1467

    CAS  PubMed  Google Scholar 

  • Bell F, Kenyon J, Robinson PH (1926) CLX. Investigations in the Diphenyl Series. Part I. Migration Reactions. J Chem Soc (Lond) pp 1239–1247

    Article  Google Scholar 

  • Burns JJ, Conney AH (1965) Biochemical studies with phenacetin and related compounds. Proc Eur Soc Study of Drug Toxicity 6: 76–81

    CAS  Google Scholar 

  • Calder IC, Creek MJ, Williams PJ, Funder CC, Green CR, Ham KN, Tange JD (1973) N-Hydroxylation of p-acetophenetidide as a factor of nephrotoxicity. J Med Chem 16: 499–502

    Article  CAS  Google Scholar 

  • Calder IC, Goss DE, Williams PJ, Funder CC, Green CR, Ham KN, Tange JD (1976) Neoplasia in the rat induced by N-hydroxyphenacetin, a metabolite of phenacetin. Pathology 8: 1–6

    Article  CAS  Google Scholar 

  • Evelyn KA, Malloy HT (1938) Microdetermination of oxyhemoglobin, methemoglobin, and sulfhemoglobin in a single sample of blood. J Biol Chem 126: 655–662

    CAS  Google Scholar 

  • Eyer P, Kiese M, Lipowsky G, Weger N (1974) Reaction of 4-dimethylaminophenol with hemoglobin, and autoxidation of 4-dimethylaminophenol. Chem Biol Interact 8: 41–59

    Article  CAS  Google Scholar 

  • Fischbach T (1975) N-Hydroxyphenacetin, Darstellung, Biosynthese und Biotransformation. Diplomarbeit LM-Universität München 1975

  • Fischbach T, Hertle H, Kiese M, Lenk W, Sterzl H, Meister P (1982) Toxicity of certain polycyclic and monocyclic N-arylacetohydroxamic acids in rats. In: Kehl H (ed) Chemistry and biology of hydroxamic acids. S. Karger, New York and Basel, pp 140–148

    Google Scholar 

  • Fischbach T, Lenk W, Sackerer D (1977) Additional routes in the metabolism of phenacetin. In: Jollow DJ, Kocsis JJ, Snyder R, Vainio H (eds) Biological reactive intermediates. Formation, Toxicity, and Inactivation. Plenum Press New York and London, pp 380–386

    Chapter  Google Scholar 

  • Food and Drug Administration Advisory Committee on Protocols for Safety Evaluation (1971) Panel on carcinogenesis report on cancer testing in the safety evaluation of food additives and pesticides. Toxicol Appl Pharmacol 20: 419–438

    Article  Google Scholar 

  • Forrester AR, Ogilvy MM, Thomson RH (1970) Mode of action of carcinogenic amines. Part I. Oxidation of N-arylhydroxamic acids. J Chem Soc (C):1081–1083

  • Fries W, Kiese M, Lenk W (1973) Oxidation of polycyclic N-arylacetamides to glycolamides and hydroxamic acids in rabbits. Xenobiotica 3: 525–540

    Article  CAS  Google Scholar 

  • Gebhard R (1980) Chemie and Biochemie von N-hydroxy-N-acetyl-p-Aminophenol. Diplomarbeit Universität München

  • Gutman HR, Galitski SB, Foley WA (1967) The conversion of non-carcinogenic aromatic amides to carcinogenic arylhydroxylamines by synthetic N-hydroxylation. Cancer Res 27: 1443–1455

    Google Scholar 

  • Gutman HR, Leaf DS, Yost Y, Rydell RE, Chen CC (1970) Structure-activity relationships of N-acylarylhydroxylamines in the rat. Cancer Res 30: 1485–1498

    Google Scholar 

  • Haworth RD, Lapworth A (1921) LXXXV. Reduction of emulsified nitrocompounds. Part II. Some extensions of the method. J Chem Soc (Lond) 119: 768–777

    Article  CAS  Google Scholar 

  • Herr F, Kiese M (1959) Bestimmung von Nitrosobenzol im Blute. Naunyn-Schmiedeberg's Arch Exp Path Pharmakol 235: 351–353

    CAS  Google Scholar 

  • Heubner W, Wahler B, Ziegler C (1953) Über die Bildung von Hämoglobin durch acylierte Phenylhydroxylamine. Z Physiol Chem 295: 397–403

    Article  CAS  Google Scholar 

  • Hinson JA, Mitchell JR, Jollow DJ (1975) Microsomal N-hydroxylation of p-chloroacetanilide. Mol Pharmacol 11: 462–469

    CAS  Google Scholar 

  • Hinson JA, Mitchell JR, Jollow DJ (1976a) N-Hydroxylation of p-chloroacetanilide in hamsters. Biochem Pharmacol 25: 599–601

    Article  CAS  Google Scholar 

  • Hinson JA, Mitchell JR (1976b) N-Hydroxylation of phenacetin by hamster liver microsomes. Drug Metab Disp 4: 430–435

    CAS  Google Scholar 

  • Hultengren N, Lagergren C, Ljungquist A (1965) Carcinoma in the renal pelvis in renal papillary necrosis. Acta Chir Scand 130: 314–320

    CAS  PubMed  Google Scholar 

  • Hustedt G, Kiese M (1959) Umsetzungen von Acetanilid und Acetylphenylhydroxylamin im Organismus. Arch Exp Pathol Pharmakol 236: 435–448

    CAS  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  • Johansson SL (1981) Carcinogenicity of analgesics: long-term treatment of Sprague-Dawley rats with phenacetin, phenazone, caffeine and paracetamol (acetamidophen). Int J Cancer 27: 521–529

    Article  CAS  Google Scholar 

  • Kiese M (1966) The biochemical production of ferrihemoglobin-forming derivatives from aromatic amines, and mechanisms of ferrihemoglobin formation. Pharmacol Rev 18: 1091–1161

    CAS  PubMed  Google Scholar 

  • Kiese M (1974) Methemoglobinemia: A comprehensive treatise. CRC Press, Cleveland p 260

    Google Scholar 

  • Kiese M, Lenk W (1969) Oxidation of acetanilides to glycolanilides and oxanilic acids in rabbits. Biochem Pharmacol 18: 1325–1333

    Article  CAS  Google Scholar 

  • Kiese M, Lenk W (1971) Metabolites of 4-chloroaniline and chloroacetanilides produced by rabbits and pigs. Biochem Pharmacol 20: 379–391

    Article  CAS  Google Scholar 

  • Kiese M, Plattig KH (1959) Hämiglobinbildung durch Benzoylphenylhydroxylamin. Naunyn-Schmiedeberg's Arch Exp Pathol Pharmakol 235: 373–380

    CAS  Google Scholar 

  • Lenk W, Scharmer U (1980) Reaction of microsomal and cytosolic enzymes with N-arylacetohydroxamic acids. Xenobiotica 10: 573–591

    Article  CAS  Google Scholar 

  • Lees WA, Burawoy A (1963) Effect of hydrogen bonding on the electronic spectra of organic molecules. Tetrahedron 19: 419–438

    Article  CAS  Google Scholar 

  • Lotlikar PD, Miller EC, Miller JA, Margreth A (1965) The enzymatic reduction of the N-hydroxy derivatives of 2-acetylaminofluorene and related carcinogens by tissue preparations. Cancer Res 25: 1743–1752

    CAS  PubMed  Google Scholar 

  • Miller EC, Miller JA, Hartmann HA (1961a) N-Hydroxy-2-acetylaminofluorene: A metabolite of 2-acetylaminofluorene with increased carcinogenic activity in the rat. Cancer Res 21: 815–824

    CAS  PubMed  Google Scholar 

  • Miller JA, Wyatt CS, Miller EC, Hartmann HA (1961b) The N-hydroxylation of 4-acetylaminobiphenyl by the rat and dog and the strong carcinogenicity of N-hydroxy-4-acetylaminobiphenyl in the rat. Cancer Res 21: 1465–1473

    CAS  Google Scholar 

  • Miller JA, Enomoto M, Miller EC (1962) The carcinogenicity of small amounts of N-hydroxy-2-acetylaminofluorene and its cupric chelate in the rat. Cancer Res 22: 1381–1388

    CAS  Google Scholar 

  • Miller EC, Miller JA, Enomoto M (1964) The comparative carcinogenicities of 2-acetylaminofluorene and its N-hydroxy metabolite in mice, hamsters, and guinea pigs. Cancer Res 24: 2018–2026

    CAS  PubMed  Google Scholar 

  • Miller EC, Lotlikar PD, Pitot HC, Fletcher TL, Miller JA (1966) N-Hydroxy metabolites of 2-acetylaminophenanthrene and 7-fluoro-2-acetylaminofluorene as proximate carcinogens in the rat. Cancer Res 26: 2239–2247

    CAS  PubMed  Google Scholar 

  • Misra HP, Fridovich I (1972) The generation of superoxide radical during the autoxidation of hemoglobin. J Biol Chem 247: 6960–6962

    CAS  PubMed  Google Scholar 

  • Nery R (1971) The possible role of N-hydroxylation in the biological effects of phenacetin. Xenobiotica 1: 27–31

    Article  Google Scholar 

  • Neunhoeffer O, Ruske E (1961) Common disproportionation of nitroso compounds and aldehydes under the influence of aluminium alcoholate. A contribution to the mechanism of the alcoholate catalysis. Chem Ber 94: 623–627

    Article  CAS  Google Scholar 

  • Poirier LA, Miller JA, Miller EC (1963) The N- and ring-hydroxylation of 2-acetylaminofluorene and the failure to detect N-acetylation of 2-aminofluorene in the dog. Cancer Res 23: 790–800

    CAS  PubMed  Google Scholar 

  • Potter WZ, Davis DC, Mitchell JR, Jollow DJ, Gillette JR, Brodie BB (1973) Acetaminophen-induced hepatic necrosis. III. Cytochrome P-450-mediated covalent binding in vitro. J Pharmacol Exp Ther 187: 203–210

    CAS  PubMed  Google Scholar 

  • Rising A (1904) Über die Methyl- und Aethyl-Aether des p-Oxyphenylhydroxylamins und die daraus dargestellten Azoxyverbindungen. Ber Dtsch Chem Ges 37: 43–47

    Article  CAS  Google Scholar 

  • Schmähl D, Reiter A (1954) Fehlen einer cancerogenen Wirkung beim Phenacetin. Arzneim Forsch 4: 404–405

    Google Scholar 

  • Smith PK (1958) Acetophenetidin, a critical bibliographic review. Interscience Publishers, London-New York, pp 132–133

    Google Scholar 

  • Spühler O, Zollinger HU (1953) Die chronische interstitielle Nephritis. Z Klin Med 151: 1–50

    PubMed  Google Scholar 

  • Weisburger JH, Grantham PH, Weisburger EK (1969) The transport of chemical carcinogens by blood. Metabolites of N-2-fluorenylacetamide and N-hydroxy-N-2-fluorenylacetamide as a function of time. In: Bergman ED, Pullman B (eds) Physico-chemical mechanisms of carcinogenesis. Proc. Intern Sympos, Israel, Academy of Sciences and Humanities, Jerusalem, pp 262–283

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Institut für Pharmakologie und Toxikologie der Universität München, Nußbaumstr. 26, D-8000, München 2, Germany

    Tilman Fischbach, Hildegard Hertle, Manfred Kiese, Werner Lenk & Heidrun Sterzl

  2. Pathologisches Institut der Universität München, Thalkirchner Str. 36, D-8000, München 2, Germany

    Peter Meister

Authors
  1. Tilman Fischbach
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hildegard Hertle
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Manfred Kiese
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Werner Lenk
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Heidrun Sterzl
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Peter Meister
    View author publications

    You can also search for this author in PubMed Google Scholar

Additional information

Professor M. Kiese deceased February 22nd, 1983

Rights and permissions

Reprints and permissions

About this article

Cite this article

Fischbach, T., Hertle, H., Kiese, M. et al. N-Hydroxy-N-arylacetamides. Arch Toxicol 56, 96–105 (1984). https://doi.org/10.1007/BF00349079

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00349079

Key words

Search

Navigation