Mutation spectra in Salmonella of analogues of MX: Implications of chemical structure for mutational mechanisms
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|Julkaisu||Mutation Research: Fundamental and Molecular Mechanisms of Mutagenesis|
|DOI - pysyväislinkit|
|Tila||Julkaistu - 20 syyskuuta 2000|
We determined the mutation spectra in Salmonella of four chlorinated butenoic acid analogues (BA-1 through BA-4) of the drinking water mutagen 3- chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone (MX) and compared the results with those generated previously by us for MX and a related compound, MCF. We then considered relationships between the properties of mutagenic potency and mutational specificity for these six chlorinated butenoic acid analogues. In TA98, the three most potent mutagens, BA-3, BA-4, MX, and the organic extract, all induced large percentages of complex frameshifts (33- 67%), which distinguish these agents from any other class of compound studied previously. In TA100, which has only GC sites for mutation recovery, >71% of the mutations induced by all of the agents were GC→TA transversions. The availability of both GC and TA sites for mutation in TA104 resulted in greater distinctions in mutational specificity than in TA100. MX targeted GC sites almost exclusively (98%); the structurally similar BA-4 and BA-2 produced mutations at similar frequencies at both GC and AT sites; and the structurally similar BA-3 and BA-1 induced most mutations at AT sites (69%). Thus, large variations in structural properties influencing relative mutagenic potency appeared to be distinct from the more localized similar structural features influencing mutagenic specificity in TA104. Among a set of physicochemical properties examined for the six butenoic acids, a significant correlation was found between pK(a) and mutagenic potency in TA100, even when the unionized fraction of the activity dose was considered. In addition, a correlation in CLOGP for BA-1 to BA-4 suggested a role for bioavailability in determining mutagenic potency. These results illustrate the potential value of structural analyses for exploring the relationship between chemical structure and mutational mechanisms. To our knowledge, this is the first study in which such analyses have been applied to structural analogues for which both mutagenic potency and mutation spectra date were available.