MUTATIONS INDUCED BY MONOFUNCTIONAL AND BIFUNCTIONAL PHOSPHORAMIDE MUSTARDS IN SUPF TRANSFER-RNA GENE

The relative mutagenicity, nature of the mutations and the sequence sp ecificity of mutations induced by the bifunctional alkylating agent, p hosphoramide mustard (PM) and a monofunctional derivative, dechloroeth yl phosphoramide mustard (dePM), were analyzed by the Ames test and by an in vitro shuttle vector mutagenesis assay. Both PM and dePM increa sed the mutation frequency above background in either assay. However, on an equimolar basis, dePM was less mutagenic than PM. In the in vitr o shuttle vector mutagenesis assay, sequencing demonstrated that about 40% of the mutant plasmids contained more than one mutation in the su pF tRNA gene segment of the plasmid. About 70% of the mutations observ ed in dePM-treated plasmids were single base substitutions with A:T an d G:C base pairs being mutated at equivalent rates. In contrast, only about 50% of the mutations observed in PM-treated plasmids were single base substitutions, 80% of which involved G:C base pairs. Single base deletions and insertions were found in approximately equal proportion s with both compounds; however, these lesions were in greater abundanc e in PM-treated plasmids. Putative hot-spots for mutation in the supF tRNA gene included base pairs at positions 102 and 110 for PM and posi tions 170 and 171 for dePM. (C) 1997 Elsevier Science B.V.