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Mutagenic activity of oxathiolane steroids: structural requirement for the genotoxic activity in Salmonella and E.
1Department of Biochemistry, Faculty of Life Sciences, Aligarh Muslim University, India.
Abstract:
Oxathiolanes and disulfonyl derivatives of steroids were tested for mutagenic activity in the Ames tester strains. The test compounds exhibited mutagenic activity without metabolic activation although metabolic activation markedly enhanced their activity. A significant decrease in the survival of the radiation-sensitive mutants recA, lexA and rer of E. coli was observed as compared to their wild-type counterpart in the presence of the test steroid. Structural features which appear to be crucial for the mutagenic activity in these steroidal drugs are: (i) an electron-donating group at position 3, and (ii) a bulky group anchored at the 5th and 6th positions. The test steroids appear to damage DNA which in turn initiates the SOS repair with the concomitant induction of mutation.
Insights
Steroidal drug derivatives showed mutagenic activity in bacterial tests, with enhanced effects after metabolic activation. These compounds damage DNA, triggering SOS repair and mutation, particularly in radiation-sensitive bacterial strains.
Area of Science:
- Biochemistry
- Molecular Biology
- Genetics
Background:
- Steroids are a class of organic compounds with diverse biological functions.
- Mutagenic compounds can cause DNA damage and lead to genetic mutations.
- Steroidal derivatives are synthesized for various therapeutic purposes, necessitating safety evaluations.
Purpose of the Study:
- To evaluate the mutagenic potential of oxathiolanes and disulfonyl derivatives of steroids.
- To investigate the role of metabolic activation in the mutagenicity of these steroidal compounds.
- To identify structural features contributing to the mutagenic activity of these steroids.
Main Methods:
- Mutagenicity testing using Ames tester strains of bacteria.
- Assessment of bacterial survival in radiation-sensitive mutants (recA, lexA, rer) and wild-type E. coli.
- Analysis of structure-activity relationships for mutagenic potential.
Main Results:
- The tested steroidal compounds exhibited inherent mutagenic activity.
- Metabolic activation significantly enhanced the mutagenic activity of the test compounds.
- A notable decrease in the survival rate of radiation-sensitive E. coli mutants was observed in the presence of the steroids.
- Specific structural features, including an electron-donating group at position 3 and a bulky group at positions 5 and 6, were identified as crucial for mutagenicity.
Conclusions:
- Oxathiolanes and disulfonyl steroid derivatives possess mutagenic properties.
- These steroids induce DNA damage, leading to SOS repair and subsequent mutations.
- The identified structural features are key determinants of mutagenic activity in these steroidal drugs.