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Clavine alkaloids and derivatives as mutagens detected in the Ames test
1Department of Toxicology, Johannes Gutenberg-Universität, Mainz, Germany.
Abstract:
Eight cytostatic clavines were investigated for mutagenicity in Salmonella typhimurium (reversion of the his-strains TA98, TA100, TA102 and TA1537), directly and in the presence of a mammalian xenobiotic metabolizing system, S9 (NADPH-fortified postmitochondrial fraction of liver homogenate from Aroclor 1254-treated rats). Four compounds (festuclavine, 17-bromofestuclavine, 1-allylelymoclavine and 1-methyllysergol methyl ether) were direct mutagens, whose activity was enhanced in the presence of S9. The other compounds (1-cyclopentylfestuclavine, 13-bromo-1-cyclopropylmethylfestuclavine, 6-cyano-1-propyl-6-norfestuclavine and 6-allyl-1-propyl-6-norfestuclavine) showed mutagenic effects only in the presence of S9, as previously observed with other clavines (agroclavine and its 1-propyl and 1-pentyl derivatives). Thus, all investigated clavines may be metabolized to mutagenic products by mammalian enzymes. Bacteriotoxic activities did not correlate with mutagenic activities. The bacteriotoxicity of several clavines was reduced in the presence of S9. The results are discussed with regard to the potential therapeutic use of clavine alkaloids as antimicrobial and antineoplastic agents.
Insights
All eight cytostatic clavines showed mutagenic potential in Salmonella typhimurium assays. Four compounds were direct mutagens, while others required mammalian enzymes (S9) for activation, indicating potential therapeutic risks.
Area of Science:
- Pharmacology
- Toxicology
- Microbiology
Background:
- Clavine alkaloids possess cytostatic properties with potential therapeutic applications.
- Investigating the mutagenicity of clavines is crucial for assessing their safety profile.
Purpose of the Study:
- To evaluate the mutagenicity of eight cytostatic clavine compounds.
- To determine if mammalian metabolic activation influences clavine mutagenicity.
- To assess the correlation between bacteriotoxicity and mutagenicity of clavines.
Main Methods:
- Bacterial mutagenicity testing using Salmonella typhimurium reversion assays (strains TA98, TA100, TA102, TA1537).
- Assays were conducted directly and in the presence of a mammalian xenobiotic metabolizing system (S9).
- Bacteriotoxicity was assessed and compared with mutagenic activity.
Main Results:
- Four clavines (festuclavine, 17-bromofestuclavine, 1-allylelymoclavine, 1-methyllysergol methyl ether) were direct mutagens.
- The remaining four clavines exhibited mutagenicity only after metabolic activation by S9.
- All tested clavines demonstrated mutagenic potential following metabolic activation.
- Bacteriotoxic activity did not correlate with mutagenicity, and S9 reduced the toxicity of some clavines.
Conclusions:
- All investigated clavines can be metabolized into mutagenic compounds by mammalian enzymes.
- The findings suggest caution regarding the therapeutic use of clavine alkaloids due to mutagenic potential.
- Further research is needed to balance the antimicrobial/antineoplastic potential with the observed mutagenicity.