Mutation spectra in Salmonella of analogues of MX: implications of chemical structure for mutational mechanisms

We determined the mutation spectra in Salmonella of four chlorinated buteno ic acid analogues (BA-1 through BA-4) of the drinking water mutagen 3-chlor o-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 W e then considered relationships between the properties of mutagenic potency and mutational specificity for these six chlorinated butenoic acid analogu es. In TA98, the three most potent mutagens, BA-3, BA-4, MX, and the organi c extract, all induced large percentages of complex frameshifts (33-67%), w hich distinguish these agents from any other class of compound studied prev iously. In TA100, which has only GC sites for mutation recovery, >71% of th e mutations induced by all of the agents were GC-->TA transversions. The av ailability of both GC and TA. sites for mutation in TA104 resulted in great er distinctions in mutational specificity than in TA100. MX targeted GC sit es almost exclusively (98%); the structurally similar BA-4 and BA-2 produce d mutations at similar frequencies at both GC and AT sites; and the structu rally similar BA-3 and BA-1 induced most mutations at AT sites (69%). Thus, large variations in structural properties influencing relative mutagenic p otency appeared to be distinct from the more localized similar structural f eatures influencing mutagenic specificity in TA104. Among a set of physicoc hemical properties examined for the six butenoic acids, a significant corre lation was found between pK(a) and mutagenic potency in TA100, even when th e unionized fraction of the activity dose was considered. In addition, a co rrelation in CLOGP for BA-1 to BA-4 suggested a role for bioavailability in determining mutagenic potency. These results illustrate the potential valu e of structural analyses for exploring the relationship between chemical st ructure and mutational mechanisms. To our knowledge, this is the first stud y in which such analyses have been applied to structural analogues for whic h both mutagenic potency and mutation spectra date were available. Publishe d by Elsevier Science B.V.