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Abstract:
The cytotoxic and mutagenic specificity of two therapeutically employed psoralens was examined in several Ames Salmonella typhimurium strains with near ultraviolet light (UVA, 320-400 nm) activation. Photomutagenic activity of 8-methoxypsoralen (8MOP) and 4,5',8-trimethylpsoralen (TMP) was found to be sequence-specific, and additionally was dependent on the level of DNA-repair proficiency. Base-pair substitution photomutagenesis in hisG46 appeared to require plasmid pKM101-mediated "error-prone" repair. Frameshift photomutagenesis was observed in all hisC3076 strains but not in hisD3052 strains. Frameshift mutagenic activity in hisC3076 was enhanced in the absence of uvrB excision repair and increased further by plasmid pKM101. Phototoxicity was essentially identical in hisC3076, hisD3052 and hisG46 strains; uvrB- excision-repair-deficient bacteria were considerably more susceptible to lethal effects than wild-type parental strains, while the presence of pKM101 had no apparent effect on survival. Finally, the data show that psoralens are potent frameshift photomutagens in Salmonella hisC3076 strains and demonstrate the potential utility of these strains in evaluating photomutagenic and phototoxic activity of new furocoumarin derivatives.
Insights
Two psoralens, 8-methoxypsoralen (8MOP) and 4,5',8-trimethylpsoralen (TMP), show sequence-specific photomutagenic activity in Salmonella strains. Their mutagenicity and phototoxicity depend on DNA repair proficiency and specific genetic mutations.
Area of Science:
- Photobiology
- Molecular Toxicology
- Microbial Genetics
Background:
- Psoralens are photosensitizing compounds used therapeutically.
- Understanding their mutagenic and cytotoxic effects is crucial for safety assessments.
- DNA repair mechanisms significantly influence cellular responses to psoralen-induced DNA damage.
Purpose of the Study:
- To investigate the cytotoxic and mutagenic specificity of 8-methoxypsoralen (8MOP) and 4,5",8-trimethylpsoralen (TMP).
- To evaluate the role of DNA repair proficiency in psoralen-induced photomutagenesis and phototoxicity.
- To assess the utility of specific Ames Salmonella typhimurium strains for testing furocoumarin derivatives.
Main Methods:
- Exposure of Ames Salmonella typhimurium strains (hisG46, hisC3076, hisD3052) to 8MOP and TMP.
- Activation of psoralens using near ultraviolet light (UVA, 320-400 nm).
- Assessment of base-pair substitution and frameshift mutations, and bacterial survival rates, considering DNA repair genes (uvrB) and plasmids (pKM101).
Main Results:
- Photomutagenic activity was sequence-specific and dependent on DNA repair proficiency.
- Base-pair substitution photomutagenesis required pKM101-mediated "error-prone" repair.
- Frameshift photomutagenesis occurred in hisC3076 strains, enhanced by the absence of uvrB repair and presence of pKM101.
- Phototoxicity was similar across strains, but uvrB-deficient bacteria were more susceptible to lethal effects.
Conclusions:
- Psoralens are potent frameshift photomutagens in Salmonella hisC3076 strains.
- The study highlights the importance of DNA repair pathways in modulating psoralen genotoxicity.
- Ames strains with specific repair deficiencies are valuable tools for evaluating photomutagenic and phototoxic potential of furocoumarins.