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DNA damage in tissues of rat treated with potassium canrenoate
Antonietta Martelli1, Roberto Carrozzino, Francesca Mattioli
1Department of Internal Medicine, Division of Clinical Pharmacology and Toxicology, University of Genoa, Tossicologia Clinica, Viale Benedetto XV 2, I-16132, Genoa, Italy.
Abstract:
Potassium canrenoate (PC), a competitive aldosterone antagonist previously found to increase tumor incidence in rats and to produce genotoxic effects in in vitro systems, was examined in rats to acquire information on its genotoxic activity in vivo. Intragastric administration of 1/2 LD50 produced, as revealed by the Comet assay, a modest but statistically significant increase in the frequency of DNA lesions in liver but not in thyroid and bone marrow of male rats, and in thyroid and bone marrow but not in liver of female rats. In contrast with the frankly positive responses observed in primary cultures of rat hepatocytes (Martelli et al., Mutagenesis 14 (1999) 463-472) any evidence of DNA repair and micronuclei formation was absent in liver of rats treated with 1/2 LD50, and initiation of enzyme-altered liver preneoplastic lesions did not occur in the liver of rats given 100 mg/kg PC once a week for 6 successive weeks. A high and dose-dependent frequency of DNA lesions was found to occur in testes and ovaries of rats given single doses ranging from 1/8 to 1/2 LD50.
Insights
Potassium canrenoate (PC) showed genotoxic activity in vivo, causing DNA damage in specific organs of male and female rats. Further studies revealed DNA lesions in testes and ovaries, indicating potential reproductive toxicity.
Area of Science:
- Toxicology
- Genetics
- Pharmacology
Background:
- Potassium canrenoate (PC) is an aldosterone antagonist.
- Previous studies indicated PC increases tumor incidence in rats and shows genotoxicity in vitro.
- In vivo genotoxicity data for PC was lacking.
Purpose of the Study:
- To investigate the in vivo genotoxic activity of Potassium canrenoate (PC) in rats.
- To assess DNA damage in various organs following PC administration.
- To evaluate the potential for PC to induce preneoplastic lesions.
Main Methods:
- Rats were administered PC intragastrically at 1/2 LD50.
- The Comet assay was used to detect DNA lesions in liver, thyroid, and bone marrow.
- DNA repair, micronuclei formation, and enzyme-altered preneoplastic lesions were assessed in the liver.
- DNA lesions in testes and ovaries were examined after single doses.
Main Results:
- A modest, statistically significant increase in DNA lesions was observed in the liver of male rats and in the thyroid and bone marrow of female rats.
- No evidence of DNA repair or micronuclei formation was found in the liver.
- PC did not initiate enzyme-altered liver preneoplastic lesions.
- A high, dose-dependent frequency of DNA lesions occurred in the testes and ovaries.
Conclusions:
- Potassium canrenoate exhibits in vivo genotoxic activity, with organ-specific effects.
- The compound induced significant DNA damage in reproductive organs (testes and ovaries).
- Further investigation into the reproductive toxicity of PC is warranted.