Use of the DNA-repair host-mediated assay for determining the organ distribution of genotoxic factors in mice treated orally with nitro-aromatic compounds

• Published in: Mutation Research/Environmental Mutagenesis and Related Subjects Vol. 164; no. 1; pp. 9 - 17
• Main Authors: Knasmüller, S., Kerklaan, P., Mohn, G.R.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.02.1986
• Subjects: 5-Amino-3-((5-nitro-2-furyl)vinyl)-1,2,4-oxadiazole - analysis; 5-Amino-3-((5-nitro-2-furyl)vinyl)-1,2,4-oxadiazole - pharmacology; Aniline Compounds - analysis; Animals; Anthelmintics - analysis; Anthelmintics - pharmacology; Antiprotozoal Agents - analysis; Antiprotozoal Agents - pharmacology; Diphenylamine - analogs & derivatives; Diphenylamine - analysis; Diphenylamine - pharmacology; DNA Repair - drug effects; Escherichia coli - drug effects; Female; Isothiocyanates; Metronidazole - analysis; Metronidazole - pharmacology; Mice; Mutagenicity Tests; Nitrofurans - analysis; Thiocyanates - analysis; Thiocyanates - pharmacology; Tissue Distribution; PBS; NRS-agar; amoscanate; metronidazole; SQ 18 506; PEP-S
• ISSN: 0165-1161; 0027-5107
• DOI: 10.1016/0165-1161(86)90037-3

The distribution of genotoxic factors in various organs of mice treated orally with nitro-aromatic compounds of actual or potential use as chemotherapeutic (antiprotozoal and anthelminthical) agents was investigated in the DNA-repair host-mediated assay, with mice as host animals and a pair of E. coli K12 strains differing in DNA-repair capacity as indicators of genotoxicity. The test substances were derivatives of nitroimidazole (metronidazole), nitrofuran (SQ 18 506) and nitrodiphenylamine (amoscanate). Animal-mediated assays were performed by injecting mixtures of the two E. coli strains both intravenously and orally into mice, which were subsequently treated with the test chemicals, and from which the differential survival of indicator bacteria present in liver, lungs, spleen, kidneys, stomach, small intestine, colon and the blood stream was determined on selective agar medium. The same strains and selection procedures were used for assessing the genotoxic activity of the compounds in vitro. All three compounds displayed genotoxic activity in vitro, the order of potency on the basis of exposure concentration being SQ 18 506 > metronidazole > amoscanate. In the animal-mediated assays the same ranking order of genotoxic activity was observed, but the exposure levels required to produce significant genotoxic effects in vivo were (substantially) higher than in the in vitro tests: SQ 18 506 was active at 0.1 mg/kg body weight, metronidazole at 4 mg/kg, and amoscanate at dosages higher than 10 mg/kg. In host-mediated assays the highest genotoxic activity for all three chemicals was observed in organs of the gastro-intestinal tract (usually in the stomach). All three chemicals also induced genotoxic effects in organs remote from the gastro-intestinal tract although with substantially lower activity, the order of potency being again SQ 18 506 > metronidazole > amoscanate. In the case of SQ 18 506 and metronidazole, dose-dependent genotoxic activities were observed in liver, spleen, lungs, kidneys and the blood stream, with no clear indication of a preferential target or non-target organ, while the minor genotoxic effects of amoscanate were restricted to bacteria present in the blood stream. This can be taken as an indication that the substances (or active metabolites thereof) have been transported from the intestinal tract into the blood stream and distributed evenly in organ tissues, without an indication of organ specific deactivation during the time periods (< 180 min) presently investigated. With the present set of bacterial indicators, which obviously do possess nitroreductases, it is not possible to determine whether the genotoxic activities formed in the various organs of treated mice are due to the unmetabolized parent chemical or to active mammalian metabolites. This problem is presently under investigation.