Effects of metyrapone on microsomal-dependent Salmonella mutagenesis. Studies with chloroallyl ethers and model compounds.
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.
D000498:Allyl Compounds; D000818:Animals; D002219:Carbamates; D065607:Cytochrome P-450 Enzyme Inhibitors; D006540:Herbicides / Q000378:metabolism; D006843:Hydrocarbons, Chlorinated / Q000032:analysis / Q000302:isolation & purification*; D066298:In Vitro Techniques; D008797:Metyrapone / Q000494:pharmacology*; D008862:Microsomes, Liver / Q000378:metabolism*; D009152:Mutagenicity Tests; D009153:Mutagens / Q000378:metabolism*; D051381:Rats; D012475:Salmonella / Q000235:genetics*
D000498:Allyl Compounds; D002219:Carbamates; D065607:Cytochrome P-450 Enzyme Inhibitors; D006540:Herbicides; D006843:Hydrocarbons, Chlorinated; D009153:Mutagens; C040100:3-(2-chloroethoxy)-1,2-dichloropropene; D008797:Metyrapone