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Gene expression changes induced by bismuth in a macrophage cell line
Nils E Magnusson1, Agnete Larsen, Jørgen Rungby
1Molecular Diagnostic Laboratory, Department of Clinical Biochemistry, Aarhus University Hospital, Denmark.
Cell and Tissue Research
|May 25, 2005
Summary
Bismuth accumulation in macrophages causes cell death, with increased metallothionein and glycolytic enzyme induction. This suggests a time-dependent molecular cascade leading to cell dormancy and eventual death.
Area of Science:
- Toxicology
- Cell Biology
- Biochemistry
Background:
- Bismuth compounds are used in medicine, but their cellular effects require detailed investigation.
- Understanding bismuth's impact on macrophages is crucial for assessing its safety and therapeutic potential.
Purpose of the Study:
- To elucidate the cellular and molecular mechanisms underlying bismuth toxicity in macrophages.
- To investigate the time- and dose-dependent effects of bismuth on macrophage viability and gene expression.
Main Methods:
- Autometallography to visualize bismuth.
- Cell viability assays to quantify cell death.
- TUNEL assay to detect DNA fragmentation.
- Microarray analysis to assess gene expression profiles.
Main Results:
- Bismuth accumulated in macrophage lysosomes in a time- and dose-dependent manner.
- Bismuth exposure significantly reduced cell viability and induced DNA damage (TUNEL-positive cells).
- Microarray analysis revealed bismuth as a potent metallothionein inducer and highlighted the upregulation of glycolytic enzymes and BCL2/adenovirus E1B 19-kDa-interacting protein 3 (Bnip3), suggesting hypoxia-like stress and a potential role in cell death.
Conclusions:
- Bismuth induces toxicity in macrophages through lysosomal accumulation and DNA damage.
- Bismuth triggers a "hypoxia-like" stress response, involving metallothionein induction and altered glycolytic enzyme expression.
- Up-regulation of Bnip3 indicates its involvement in bismuth-induced cell death, potentially via a caspase-3 independent pathway.