Mutation spectra of the drinking water mutagen 3-chloro-4-methyl-5-hydroxy-2(5H)-furanone (MCF) in Salmonella TA100 and TA104: Comparison to MX

The chlorinated drinking water mutagen 3-chloro-4-methyl-5-hydroxy-2 (5H)-f uranone (MCF) occurs at concentrations similar to or greater than that of t he related furanone 3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furonone (M X). MCF and MX differ structurally only by replacement of a S-methyl in MCF with a 3-dichloromethyl in MX; yet, MCF is significantly less mutagenic th an MX and produces different adducts when reacted with nucleosides or DNA. To explore further the effects that these structural differences might have on the biological activity of MCF and MX, we determined the mutation spect ra of MCF in Salmonella strains TA100 and TA104 and of MX in strain TA104; the spectrum of MX in TA100 had been determined previously. In TA100, which presents only GC targets for mutagenesis, MCF induced primarily (75%) GC - -> TA transversions, with most of the remaining revertants (20%)) being GC --> AT transitions. This spectrum was not significantly different From that of MX in TA100 (P = 0.07). In TA104, which presents both GC and AT targets , MCF induced a lower percentage (57%) of GC --> TA transversions, with mos t of the remaining revertants (33%) being AT --> TA transversions. In contr ast, MX induced almost only (98%) GC --> TA transversions in TA104, with th e remaining revertants (2%) being AT --> TA transversions. Thus, almost all (98%) of the MX mutations were targeted at GC sites in TA104, whereas only 63% of the MCF mutations were so targeted. These results ore consistent wi th the published findings that MX:(1) forms an adduct on guanosine when rea cted with guanosine, (2) induces apurinic sites in DNA, and (3) forms a min or adduct on odenosine when reacted with adenosine or DNA. The results are also consistent with evidence that MCF forms adenosine adducts when reacted with odenosine. Our results show that the replacement of the 4-methyl in M CF with a 4-dichloromethyl to form My not only increases dramatically the m utagenic potency but also shifts significantly the mutagenic specificity fr om almost equal targeting of GC and AT sites by MCF to almost exclusive tar geting of GC sites by MX. Published 2000 WileyLiss, Inc(dagger).