Mutations induced by monofunctional and bifunctional phosphoramide mustards in supF tRNA gene.
The relative mutagenicity, nature of the mutations and the sequence specificity of mutations induced by the bifunctional alkylating agent, phosphoramide mustard (PM) and a monofunctional derivative, dechloroethyl phosphoramide mustard (dePM), were analyzed by the Ames test and by an in vitro shuttle vector mutagenesis assay. Both PM and dePM increased the mutation frequency above background in either assay. However, on an equimolar basis, dePM was less mutagenic than PM. In the in vitro shuttle vector mutagenesis assay, sequencing demonstrated that about 40% of the mutant plasmids contained more than one mutation in the supF tRNA gene segment of the plasmid. About 70% of the mutations observed in dePM-treated plasmids were single base substitutions with A:T and 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 proportions with both compounds; however, these lesions were in greater abundance in PM-treated plasmids. Putative hot-spots for mutation in the supF tRNA gene included base pairs at position 102 and 110 for PM and positions 170 and 171 for dePM.
Mudipalli
A
A
Department of Experimental Therapeutics, Roswell Park Cancer Institute, Buffalo, NY 14263-0001, USA.
Maccubbin
A E
AE
Nadadur
S S
SS
Struck
R F
RF
Gurtoo
H L
HL
D000477:Alkylating Agents / Q000633:toxicity; D001483:Base Sequence; D002460:Cell Line; D016153:Genes, Suppressor / Q000235:genetics*; D006801:Humans; D008969:Molecular Sequence Data; D009152:Mutagenicity Tests / Q000379:methods; D009153:Mutagens / Q000633:toxicity; D009154:Mutation; D010752:Phosphoramide Mustards / Q000633:toxicity*; D010957:Plasmids; D012343:RNA, Transfer / Q000235:genetics*; D013329:Structure-Activity Relationship
D000477:Alkylating Agents; D009153:Mutagens; D010752:Phosphoramide Mustards; C109610:dechloroethyl phosphoramide mustard; C096275:supF tRNA; C030090:phosphoramide mustard; D012343:RNA, Transfer