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Published on: December 7, 2010
The genetic toxicology of 5-bromodeoxyuridine in mammalian cells
1Department of Health and Human Services, U.S. Public Health Service, Food and Drug Administration, National Center for Toxicological Research, Jefferson, AR 72079.
Abstract:
The thymidine analog, BrdUrd, induces many biological responses which are of importance to the field of genetic toxicology and related disciplines. These include the induction of SCE, specific-locus mutations, and toxicity, inhibition of cell proliferation, and the expression of fragile sites in the human genome. In early models which addressed the mechanisms of the biological effects of BrdUrd exposure, two pathways were proposed to account for the induction of the biological responses. Incorporation of the enol form of BrdUrd into the nascent DNA strand after pairing with deoxyguanosine was proposed as one pathway, whereas the incorporation of BrdUrd opposite adenosine in place of thymidine was proposed as the second pathway. Many novel and sophisticated techniques have been applied to the study of the mechanism of the induction of biological effects by BrdUrd leading to a substantial increase in our understanding of these mechanisms. However, the experimental evidence clearly supports the contention that BrdUrd exerts its effects on eukaryotic cells through mechanisms similar to those originally proposed to explain the genotoxicity of BrdUrd.
Insights
The thymidine analog, bromodeoxyuridine (BrdUrd), triggers genetic toxicology responses like mutations and fragile sites. Its cellular effects are explained by proposed DNA incorporation mechanisms.
Area of Science:
- Genetic Toxicology
- Molecular Biology
- Genomics
Background:
- Bromodeoxyuridine (BrdUrd) is a thymidine analog with significant biological effects.
- These effects include induction of sister chromatid exchanges (SCE), mutations, toxicity, and fragile site expression in the human genome.
Purpose of the Study:
- To elucidate the mechanisms underlying the biological responses induced by BrdUrd exposure.
- To evaluate proposed pathways for BrdUrd's genotoxic and cellular effects.
Main Methods:
- Review and analysis of experimental evidence on BrdUrd's biological effects.
- Examination of proposed molecular mechanisms involving BrdUrd incorporation into DNA.
Main Results:
- BrdUrd induces various genetic and cellular responses, including SCE, mutations, and fragile sites.
- Two primary mechanisms for BrdUrd's action were initially proposed: incorporation opposite deoxyguanosine or adenosine.
Conclusions:
- Despite sophisticated new techniques, experimental data strongly support the original proposed mechanisms for BrdUrd's genotoxicity.
- BrdUrd exerts its effects on eukaryotic cells through pathways consistent with early genotoxicity models.
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