title: Nickel(II) genotoxicity: potentiation of mutagenesis of simple alkylating agents.
abstract: Many metals have been shown to alter the function of a wide range of enzyme systems, including those involved in DNA repair and replication. To assess the impact in vivo of such metal actions a "Microtitre" fluctuation assay was used to examine the ability of Ni(II) to act as a comutagen with simple alkylating agents. In E. coli, Ni(II) chloride potentiated the mutagenicity of methyl methanesulfonate (MMS) in polymerase-proficient strains (WP2+ and WP2-), but not in polA- strains (WP6 and WP67) or in lexA- (CM561) or recA- (CM571) strains. The absence of UV excision repair (WP2- and WP67) had little, if any, effect. An extended lag phase was seen at 2-4 h in the polA- strains following treatment with Ni(II) chloride and MMS, but normal growth resumed thereafter. Results suggested that mutations induced by MMS were fixed during log phase growth and that more than 2 h of exposure were necessary for potentiation by Ni(II) to be observed. Thus, the extended lag phase probably cannot explain the lack of potentiation. RecA-dependence of the comutagenic effect was corroborated with S. typhimurium TA1535 and TA100. Only in the pKM101 containing strain, TA100, was potentiation of ethyl methanesulfonate (EMS) and MMS by Ni(II) chloride evident. The mucAB genes carried on pKM101 increase the sensitivity of TA100 to a variety of mutagens, providing there is a functional recA gene product. Taken together, the data suggest that Ni(II) acts indirectly, as a comutagen, in bacterial systems, possibly affecting processes involving recA- and/or polA-dependent function(s).
mesh_terms: D000477:Alkylating Agents / Q000633:toxicity*; D004256:DNA Polymerase I / Q000378:metabolism; D004260:DNA Repair / Q000187:drug effects; D004357:Drug Synergism; D004926:Escherichia coli / Q000187:drug effects; D009152:Mutagenicity Tests; D009154:Mutation / Q000187:drug effects*; D009532:Nickel / Q000633:toxicity*; D011938:Rec A Recombinases / Q000502:physiology; D012486:Salmonella typhimurium / Q000187:drug effects
chemical_list: D000477:Alkylating Agents; D009532:Nickel; D011938:Rec A Recombinases; D004256:DNA Polymerase I