Mutagenicity of a series of N-alkyl-, N-hydroxyalkyl-, N-haloalkyl- and N-carboxyalkyl- N-nitrosoureas in Escherichia coli tester strains: Dependence on the uvrA DNA-repair system

Abstract

A series of N-alkyl-, N-hydroxyalkyl-, N-haloalkyl- and N-carboxyalkyl- N-nitrosoureas and some related derivatives were tested for mutagenicity in E. coli B (Arg −) H/r30R (wild-type) and its isogenic Hs30R ( uvrA) tester strains. Mutagenic potency in Hs30R, in general, appears to depend on the substituent (-OH, -OCH 3, -halogen, -COO − or -COOCH 3) on the alkyl group, rather than the chain length or branching of the alkyl group. On the other hand, mutagenic potency in the wild-type H/r30R strain depends on bulkiness of the substituent and alkyl moiety. The term “ uvrA-dependence” of mutation frequency is then defined as the ratio of the mutation frequency in Hs30R versus that in H/s30R at 1 mM dose of mutagens. Its dependence on structure is also discussed. A good correlation was found with the van der Waals volume of the substituted alkyl group, except for compounds having a carboxyalkyl or a branched alkyl group. The carboxyalkyl derivatives are the most weakly mutagenic and most seriously “ uvrA-dependent”, probably due to the negative charge of the molecule. The possibility of forming epoxides and lactones from N-hydroxyalkyl- and N-carboxyalkyl- N-nitrosoureas, respectively, and their participation in mutagenic potency are discussed. An attempt to correlate the partition property and activation rate of the N-nitrosoureas with mutagenic characteristics proved unsuccessful.