Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
9909175 | Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis | 2005 | 9 Pages |
Abstract
The first step in the activation of the anti-retroviral nucleoside analogue azidothymidine (AZT) involves its conversion to a 5â²-monophosphate. In this study, we have evaluated the role of cytosolic thymidine kinase (Tk), the major enzyme involved in phosphorylating thymidine and its analogues, in the nuclear DNA damage produced by AZT in neonatal mice. Tk+/+, Tk+/â and Tkâ/â mice were treated intraperitoneally with 200Â mg/kg/day of AZT on postnatal days 1 through 8, and micronuclei were measured in peripheral blood 24Â h after the last dose. AZT treatment increased the micronucleus (MN) frequencies to similar extents in both the reticulocytes (RETs) and normochromatic erythrocytes (NCEs) of Tk+/+ and Tk+/â mice; AZT did not increase the frequency of micronucleated RETs (MN-RETs) or micronucleated NCEs (MN-NCEs) in Tkâ/â mice. Unexpectedly, neonatal Tkâ/â mice treated with the vehicle had significantly elevated MN frequencies for both RETs and NCEs relative to Tk+/+ and Tk+/â mice (e.g., â¼3.4% MN-RETs and â¼4.8% MN-NCEs in Tkâ/â mice versus â¼0.7 and â¼ 0.6% MN-RETs and MN-NCEs in neonatal Tk+/+ mice). Additional assays performed on untreated Tkâ/â mice showed that elevated spontaneous MN frequencies persisted until at least 20 weeks of age, which approaches the average lifespan of Tkâ/â mice. These results indicate that metabolism by Tk is necessary for the genotoxicity of AZT in neonatal mice; however, the genotoxicity of AZT is not altered by reducing the Tk gene dose by half. The elevated spontaneous MN frequencies in Tkâ/â mice suggest the presence of an endogenous genotoxic activity in these mice.
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Authors
Vasily N. Dobrovolsky, Lynda J. McGarrity, Linda S. VonTungeln, Roberta A. Mittelstaedt, Suzanne M. Morris, Frederick A. Beland, Robert H. Heflich,