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Interferon-beta inhibits 7,12-dimethylbenz[a]anthracene-dependent mutagenesis in a keratinocyte cell-mediated
Abstract:
A cell-mediated mutagenesis assay employing cultured primary SENCAR keratinocytes for the metabolism of promutagens, and V-79 fibroblasts as target cells for the resulting genotoxic metabolites, was used to survey the effects of murine beta-interferon (IFN-beta) on 7,12-dimethylbenz[a]anthracene (DMBA) and benzo[a]pyrene (BP)-dependent mutagenesis and cytotoxicity. Pre-incubation of the keratinocyte cultures with greater than 100 units/ml IFN-beta, but not mock IFN, partially inhibited DMBA (25-60%) and BP (25-63%) dependent mutagenesis, but had little effect on the cytotoxicities of these agents. The level of inhibition was influenced by the length of keratinocyte pre-incubation with IFN-beta, and the concentration of IFN-beta, and the number of keratinocytes per nmol of promutagen. IFN-beta dependent inhibition of DMBA mutagenesis correlated with alterations in DMBA metabolism, including a decrease in the intra- and extracellular concentrations of the proximal promutagen (+/-) trans-DMBA-3,4-dihydrodiol.
Insights
Murine beta-interferon (IFN-beta) partially inhibited mutagenesis by 7,12-dimethylbenz[a]anthracene (DMBA) and benzo[a]pyrene (BP) in a cell-mediated assay. This effect was linked to altered DMBA metabolism, not cytotoxicity.
Area of Science:
- Toxicology
- Cell Biology
- Immunology
Background:
- Polycyclic aromatic hydrocarbons like DMBA and BP are environmental mutagens.
- Interferons modulate cellular responses to various stimuli.
- Understanding how immune modulators affect carcinogen metabolism is crucial.
Purpose of the Study:
- To investigate the effect of murine beta-interferon (IFN-beta) on DMBA and BP-induced mutagenesis and cytotoxicity.
- To explore the relationship between IFN-beta, carcinogen metabolism, and genotoxicity.
Main Methods:
- A cell-mediated mutagenesis assay using SENCAR keratinocytes and V-79 fibroblasts.
- Exposure of keratinocytes to IFN-beta prior to co-incubation with DMBA or BP.
- Measurement of mutagenesis and cytotoxicity.
- Analysis of DMBA metabolic products.
Main Results:
- IFN-beta ( > 100 units/ml) partially inhibited DMBA (25-60%) and BP (25-63%) dependent mutagenesis.
- IFN-beta had minimal impact on the cytotoxicity of DMBA and BP.
- Inhibition levels varied with IFN-beta concentration, pre-incubation time, and cell density.
- IFN-beta treatment altered DMBA metabolism, reducing key metabolites like trans-DMBA-3,4-dihydrodiol.
Conclusions:
- Murine beta-interferon can modulate the genotoxic effects of specific environmental mutagens.
- The observed inhibition of mutagenesis is likely mediated by alterations in carcinogen metabolism.
- IFN-beta's role in carcinogen-induced genotoxicity warrants further investigation.