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Abstract for IMM20306

Immunotoxicity of 3'-Azido-3'-Deoxythymidine in Female B6C3F1/N Mice (28 Days)

CASRN: 30516-87-1
Chemical Formula: C10H13N5O4
Molecular Weight: 267.2437
Report Date: November 2012

Abstract

The following abstract presents results of a study conducted by a contract laboratory for the National Toxicology Program. The findings have not been peer reviewed and were not evaluated in accordance with the levels of evidence criteria established by NTP in March 2009. The findings and conclusions for this study should not be construed to represent the views of the NTP or the U.S. Government.

3'-Azido-3'-deoxythymidine, also known as Zidovudine, is one of a class of drugs called nucleoside reverse transcriptase inhibitors, which are the most widely used therapeutic agents for the treatment of acquired immune deficiency syndrome and human immunodeficiency virus. Because HIV can infect immune cells such as CD4+ T cells, it is important to establish if drugs designed to treat the infection can impact the various functions of immune system. AZT exposure for 7 to 14 days in female mice has been demonstrated to affect the differentiation of thymus cells at daily doses ≥ 500 mg/kg (McKallip et al., 1995). In that same study, the authors reported that AZT exposure produced no effects on the cellularity or various phenotypes of the spleen.

The National Toxicology Program requested that a study be conducted to establish the potential effects of AZT on the immune system. These studies were conducted in female B6C3F1/N mice. Animals were exposed to 134, 266, or 400 mg/kg/day AZT by twice daily dosing for 28 days via oral gavage. AZT was prepared weekly as a solution in the vehicle 0.2% methylcellulose with 0.1% Tween 80.

Twice daily administration of AZT over the course of 28 days did not adversely affect the combined body weights or combined periodic body weights of female B6C3F1/N mice during the course of these studies. No effects were observed on absolute liver weights or on the weights of the major organs of the immune system, the thymus and the spleen. Relative liver weights were significantly increased at the 266 mg/kg/day dose in one study but not in a second study. Significant hematology effects indicative of macrocytic anemia were observed. Specifically, dose-related decreases in erythrocyte numbers, hemoglobin concentration, and hematocrit were observed, while dose-dependent increases were observed in mean corpuscular volume and mean corpuscular hemoglobin. Platelet concentrations were increased at the 134 and 400 mg/kg/day doses only. Mean corpuscular hemoglobin concentration, reticulocytes, total leukocyte numbers, and the absolute and percent values of lymphocytes, neutrophils, and eosinophils were all unaffected.

Total spleen cell numbers were unaffected, as were absolute values of splenic B cells, T cells, T helper and cytotoxic T cells, and macrophages. Absolute natural killer cell numbers were decreased at the 266 mg/kg/day dose level only. When evaluated in terms of percent values, mixed effects on spleen cell populations were observed. The percentage of B cells was decreased in a dose-related manner. The percentages of total T cells, TH, TCTL, and NK cells were all decreased at the 134 and 266 mg/kg/day doses but not at the 400 mg/kg/day dose.

Treatment with AZT at 400 mg/kg/day produced a decrease in the number of the antibody-forming cells/10[6] spleen cells but not in the total AFC/Spleen in the AFC assay. The sheep red blood cell enzyme-linked immunosorbent assay was unaffected. No effects were observed in the stimulated proliferative responses of spleen cells in either the mixed leukocyte response or anti-CD3 assays. In addition, innate immunity, as evaluated by examining the activity of NK cells, was not affected by treatment with AZT. Bone marrow cell numbers were significantly decreased at all AZT treatment levels, although no differences in DNA synthesis were observed when compared to vehicle control mice. In addition, the number of colony-forming units following stimulation with erythropoietin was increased at doses ≥ 266 mg/kg/day when expressed in terms of CFU-E/2x10[5] cells, while the increase was observed at the 400 mg/kg/day dose only when expressed in terms of CFU-E/Femur.

References

McKallip R.J., Nagarkatti M., & Nagarkatti P.S. (1995). Immunotoxicity of AZT: inhibitory effect on thymocyte differentiation and peripheral T cell responsiveness to gp120 of human immunodeficiency virus. Toxicol Appl Pharmacol, 131:53-62.