WHY IS 5-FLUOROURACIL A MUTAGEN

Although 5-fluorouracil causes mutations in vivo, consistent with its enol tautomer mispairing with a guanine, in vitro studies failed to illustrate such mispairing. The properties of the isolated 1-methyl derivatives of uracil (mU), 5-fluorouracil (mflU), thymine and 5-chlorouracil, and the binding energies of the 1st 2 of these, in both tautomeric forms, with 9-methyl adenine and 9-methyl guanine using the CNDO/2 method were studied. The slight tendency to be in the enol form is greater for mflU than mU. The base pairing energies favor a greater mispairing for mU than mflU. The balance of these 2 effects yields a mispairing probability of .apprx. 10-8 for mU with mflU greater by a factor of 1.3, in reasonable agreement with experimental findings. This low probability makes it hard to observe such mispairing. In the predominant keto forms, mflU binds stronger to 9-methyl adenine than mU, explaining polyfluorouridylic acid''s less ambiguous coding for phenylalanine. The order of increasing enol formation for the above isolated pyrimidines agrees with that of decreasing electron population on only N3 in the keto form, but not with that of increasing electronegativity of the 5-position substituents. The Hoogsteen hydrogen bonding scheme is more stable than the Watson-Crick one for an isolated base pair.