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Effects of metyrapone on microsomal-dependent Salmonella mutagenesis. Studies with chloroallyl ethers and model
Abstract:
Metyrapone (2-methyl-1,2-di-3-pyridyl-1-propanone, MTP) is used as an inhibitor of cytochrome P-450 enzymes, particularly those induced by phenobarbital (PB). We examined the effects of MTP on the microsomal dependent mutagenesis of a newly isolated promutagen, 3-(2-chloroethoxy)-1,2-dichloropropene (CP), three S-chloroallyl thiocarbamate herbicides, and four model promutagens aflatoxin B1 (AFB), 2-acetylaminofluorene (2AAF), 2-aminoanthracene (2AA) and benzo[a]pyrene (BP). Salmonella tester strains TA98, TA100 and TA1535 and liver microsomal preparations (S9) from rats induced with PB or Aroclor 1254 (PCB) were employed. For statistical analysis, mutagenesis data were transformed and subjected to two-way analysis of variance. Metyrapone alone was not mutagenic in the absence or presence of S9. In a dose-dependent manner, MTP inhibited mutagenesis of AFB for strains TA98 and TA100 and enhanced mutagenesis of 2AAF, 2AA and BP for these strains. 3-(2-Chloroethoxy)-1, 2-dichloropropene and the herbicides diallate, triallate and sulfallate are all chloroallyl ethers. They are similar in their mutagenesis for Salmonella with respect to strain specificity, mutagenic potency, and requirement for activation by specifically-induced microsomes. Metyrapone inhibited the mutagenesis of CP, triallate and sulfallate for strain TA100 in the presence of either PB- or PCB-induced S9, and had no apparent effect on diallate mutagenesis; the same results were obtained for TA1535 with PCB-induced S9. On this basis, the mutagenic activation of diallate appears to be different from that of the other chloroallyl ethers tested. Our results indicate that MTP can inhibit as well as enhance microsomal dependent mutagenesis for Salmonella. We conclude that MTP may be a useful tool in characterizing pathways for promutagen activation.
Insights
Metyrapone (MTP) can both inhibit and enhance mutagenicity in Salmonella, depending on the promutagen. This finding suggests MTP is a valuable tool for understanding how promutagens are activated.
Area of Science:
- Biochemistry
- Toxicology
- Genetics
Background:
- Cytochrome P-450 enzymes play a crucial role in metabolizing xenobiotics, including promutagens.
- Metyrapone (MTP) is known to inhibit cytochrome P-450 enzymes, particularly those induced by phenobarbital (PB).
- Understanding the modulation of mutagenesis by enzyme inhibitors is vital for assessing chemical safety.
Purpose of the Study:
- To investigate the effects of MTP on the microsomal activation and mutagenesis of various promutagens in Salmonella.
- To determine whether MTP inhibits or enhances the mutagenic potential of different classes of chemicals.
- To explore the utility of MTP as a tool for characterizing promutagen activation pathways.
Main Methods:
- Utilized Salmonella tester strains (TA98, TA100, TA1535) and rat liver microsomal preparations (S9) induced with phenobarbital (PB) or Aroclor 1254 (PCB).
- Assessed the mutagenicity of 3-(2-chloroethoxy)-1,2-dichloropropene (CP), three S-chloroallyl thiocarbamate herbicides, and four model promutagens (AFB1, 2AAF, 2AA, BP) in the presence and absence of MTP.
- Employed two-way analysis of variance for statistical analysis of mutagenesis data.
Main Results:
- MTP alone exhibited no mutagenicity.
- MTP dose-dependently inhibited aflatoxin B1 (AFB) mutagenesis but enhanced the mutagenesis of 2-acetylaminofluorene (2AAF), 2-aminoanthracene (2AA), and benzo[a]pyrene (BP).
- MTP inhibited the mutagenesis of CP, triallate, and sulfallate, but not diallate, suggesting different activation pathways for diallate.
Conclusions:
- Metyrapone (MTP) demonstrates a dual role, capable of both inhibiting and enhancing microsomal-dependent mutagenesis in Salmonella.
- The differential effects of MTP on various promutagens highlight its potential as a tool to elucidate complex metabolic activation pathways.
- The distinct response of diallate to MTP suggests unique mechanisms of mutagenic activation compared to other chloroallyl ethers.