Mechanistic Influences for Mutation Induction Curves after Exposure to DNA-Reactive Carcinogens

摘要: A mechanistic understanding of carcinogenic genotoxicity is necessary to determine consequences chemical exposure on human populations and improve health risk assessments. Currently, linear dose-responses are assumed for DNA reactive compounds, ignoring cytoprotective processes that may limit permanent damage. To investigate the biological significance low-dose exposures, lymphoblastoid cells were treated with alkylating agents have different mechanisms action targets: methylmethane sulfonate (MMS), methylnitrosourea (MNU), ethylmethane (EMS), ethylnitrosourea (ENU). Chromosomal damage point mutations quantified micronucleus hypoxanthine phosphoribosyltransferase forward mutation assays. MNU ENU showed dose-responses, whereas MMS EMS had nonlinear curves containing a range nonmutagenic low doses. The lowest observed effect level induction chromosomal aberrations was 0.85 μg/mL 1.40 EMS; required 1.25 before mutagenic detected. This nonlinearity could be due homeostatic maintenance by repair, which efficient at doses compounds primarily alkylate N7-G rarely attack O atoms. pragmatic threshold carcinogenicity therefore exist such genotoxins. [Cancer Res 2007;67(8):3904–11]