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Induction of micronuclei by low doses of azidothymidine (AZT)
S D Dertinger1, D K Torous, K R Tometsko
1Litron Laboratories, Rochester, NY 14620, USA.
Abstract:
The dideoxynucleoside azidothymidine (AZT; Zidovudine) was assessed for its ability to induce micronuclei in mouse erythrocytes at a low (therapeutic) dosage. Specifically, male and female BALB/c mice were treated via intraperitoneal injection 5 days a week for 2 weeks with saline or 17 mg AZT/kg body weight per day. Each animal was monitored for chemical-induced micronucleus formation over the course of the treatment regimen through the flow cytometric analysis of one million pre-dosing and one million post-dosing peripheral blood erythrocytes. No significant change in micronucleus frequencies was observed for the vehicle control group as micronuclei continued to enter the peripheral blood pool at background levels. Conversely, the AZT-treated mice exhibited a statistically significant net increase in micronucleated cells over the course of dosing as erythrocytes with a high incidence of micronuclei entered the peripheral blood pool. The advantages of high throughput scoring protocols utilizing flow cytometry are discussed.
Insights
Azidothymidine (AZT) treatment in mice significantly increased micronuclei in erythrocytes, indicating potential genotoxicity even at therapeutic doses. Flow cytometry confirmed these findings, highlighting AZT
Area of Science:
- Toxicology
- Hematology
- Genetics
Background:
- Azidothymidine (AZT; Zidovudine) is a nucleoside analog reverse transcriptase inhibitor used in HIV therapy.
- Assessing the genotoxic potential of therapeutic agents is crucial for patient safety.
- Micronuclei formation in erythrocytes is a recognized biomarker for chromosomal damage.
Purpose of the Study:
- To evaluate the clastogenic and aneugenic potential of azidothymidine (AZT) in vivo.
- To determine if a low, therapeutic dosage of AZT induces micronucleus formation in mouse erythrocytes.
Main Methods:
- BALB/c mice (male and female) received daily intraperitoneal injections of saline or 17 mg/kg AZT for two weeks.
- Peripheral blood erythrocytes were analyzed pre- and post-treatment using flow cytometry to quantify micronuclei.
- High-throughput analysis of one million erythrocytes per sample allowed for sensitive detection of genotoxic effects.
Main Results:
- Vehicle control groups showed no significant change in micronucleus frequencies, maintaining background levels.
- AZT-treated mice demonstrated a statistically significant increase in circulating micronucleated erythrocytes.
- The observed increase in micronucleated cells suggests AZT induces genotoxic effects in vivo.
Conclusions:
- Low-dose azidothymidine (AZT) administration leads to a significant increase in micronucleated erythrocytes in mice.
- These findings suggest that AZT possesses genotoxic potential, warranting careful consideration of its long-term effects.
- Flow cytometry offers an efficient, high-throughput method for assessing chemical-induced genotoxicity.