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Niacin prevents DNA strand breakage by adenosine deaminase inhibitors
1Division of Hematology/Oncology, Roger Williams General Hospital, Providence, Rhode Island 02908.
Abstract:
The adenosine deaminase inhibitors deoxycoformycin and erythro-9-(2-hydroxy-3 nonyl) adenine (EHNA) induce single-strand DNA breaks in cultured human lymphocytes. Deoxycoformycin produced a significant number of strand breaks (4-fold increase compared to controls) and EHNA induced strand breaks in a dose-dependent manner. Strand breaks stimulate repair by poly(ADP-ribosylation) which requires NAD+ as a cofactor. Niacin is a precursor of NAD+ and when preincubated with human lymphocytes prior to exposure to adenosine deaminase inhibitors, strand breakage was reduced significantly. The administration of niacin may represent an approach to decreasing the toxicity associated with these agents.
Insights
Adenosine deaminase inhibitors cause DNA strand breaks in human cells. Pre-treating cells with niacin, a NAD+ precursor, significantly reduced these breaks, suggesting a method to mitigate inhibitor toxicity.
Area of Science:
- Biochemistry
- Molecular Biology
- Pharmacology
Background:
- Adenosine deaminase (ADA) inhibitors, such as deoxycoformycin and EHNA, are used in certain therapeutic contexts.
- These inhibitors are known to affect cellular processes, but their direct impact on DNA integrity requires further elucidation.
- DNA damage and repair mechanisms are critical determinants of cellular response to xenobiotics.
Purpose of the Study:
- To investigate the effect of ADA inhibitors deoxycoformycin and EHNA on DNA integrity in human lymphocytes.
- To explore the role of poly(ADP-ribosylation) in response to ADA inhibitor-induced DNA damage.
- To evaluate the potential protective effect of niacin, a NAD+ precursor, against ADA inhibitor-induced DNA strand breaks.
Main Methods:
- Cultured human lymphocytes were treated with deoxycoformycin and EHNA.
- Single-strand DNA breaks were quantified using established assays.
- Cells were pre-incubated with niacin prior to exposure to ADA inhibitors to assess protective effects.
Main Results:
- Deoxycoformycin significantly increased single-strand DNA breaks (4-fold) in lymphocytes.
- EHNA induced DNA strand breaks in a dose-dependent manner.
- Pre-incubation with niacin markedly reduced the incidence of strand breaks induced by both inhibitors.
Conclusions:
- ADA inhibitors deoxycoformycin and EHNA induce significant single-strand DNA breaks in human lymphocytes.
- Niacin administration can mitigate this DNA damage, likely by replenishing NAD+ required for DNA repair.
- Niacin may serve as a protective agent against the genotoxic effects of ADA inhibitors.