ISSN:
1432-0738
Keywords:
N-hydroxy-N-arylacetamides
;
Arylhydroxylamines
;
Ferrihemoglobinemia
;
Carcinogenicity
;
Nephrotoxicity
Source:
Springer Online Journal Archives 1860-2000
Topics:
Medicine
Notes:
Abstract 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. 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. 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. 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. 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. 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.
Type of Medium:
Electronic Resource
URL:
http://dx.doi.org/10.1007/BF00349079
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