Research Article

Mutagenicity of zidovudine, lamivudine, and abacavir following in vitro exposure of human lymphoblastoid cells or in utero exposure of CD-1 mice to single agents or drug combinations†‡

  1. Salina M. Torres1,
  2. Dale M. Walker1,
  3. Meghan M. Carter1,
  4. Dennis L. Cook Jr.1,
  5. Consuelo L. McCash1,
  6. Edmund M. Cordova1,
  7. Ofelia A. Olivero2,
  8. Miriam C. Poirier2,
  9. Vernon E. Walker1,*

Article first published online: 14 MAR 2007

DOI: 10.1002/em.20264

Issue

Environmental and Molecular Mutagenesis

Environmental and Molecular Mutagenesis

Volume 48, Issue 3-4, pages 224–238, April - May 2007

Additional Information

How to Cite

Torres, S. M., Walker, D. M., Carter, M. M., Cook, D. L., McCash, C. L., Cordova, E. M., Olivero, O. A., Poirier, M. C. and Walker, V. E. (2007), Mutagenicity of zidovudine, lamivudine, and abacavir following in vitro exposure of human lymphoblastoid cells or in utero exposure of CD-1 mice to single agents or drug combinations. Environ. Mol. Mutagen., 48: 224–238. doi: 10.1002/em.20264

Author Information

  1. 1

    Lovelace Respiratory Research Institute, Albuquerque, New Mexico

  2. 2

    National Cancer Institute, National Institutes of Health, Bethesda, Maryland

*Lovelace Respiratory Research Institute, 2425 Ridgecrest Drive SE, Albuquerque, NM 87108, USA

  1. †

    The contents of this communication are the sole responsibility of the authors and do not necessarily represent official views of the NCI or the NIH.

  2. ‡

    Invited article on the genotoxicity of perinatal NRTI therapy.

Publication History

  1. Issue published online: 19 MAR 2007
  2. Article first published online: 14 MAR 2007

Funded by

  • National Cancer Institute. Grant Number: 1 R01 CA95741
  • National Heart, Lung, and Blood Institute. Grant Number: 1 R01 HL72727

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Keywords:

  • HPRT;
  • TK;
  • nucleoside analog;
  • transplacental

Abstract

Experiments were performed to investigate the impact of zidovudine (AZT), lamivudine (3TC), and abacavir (ABC) on cell survival and mutagenicity in two reporter genes, hypoxanthine-guanine phosphoribosyltransferase (HPRT) and thymidine kinase (TK), using cell cloning assays for assessing the effects of individual drugs/drug combinations in (1) TK6 human lymphoblastoid cells exposed in vitro and (2) splenic lymphocytes from male CD-1 mice exposed transplacentally on days 12–18 of gestation. In TK6 cells, dose-related increases in HPRT and TK mutant frequencies were found following 3 days of exposure to AZT or 3TC alone (33, 100, or 300 μM), or to equimolar amounts of AZT-3TC. Compared with single drug exposures, AZT-3TC coexposures generally yielded enhanced elevations in HPRT and TK mutant frequencies. Mutagenicity experiments with ABC alone, or in combination with AZT-3TC, were complicated by the extreme cytotoxicity of ABC. Exposure of cells either to relatively high levels of AZT-3TC short-term (100 μM, 3 days), or to peak plasma-equivalent levels of AZT-3TC for an extended period (10 μM, 30 days), resulted in similar drug-induced mutagenic responses. Among sets of mice necropsied on days 13, 15, or 21 postpartum, Hprt mutant frequencies in T-cells were significantly elevated in the AZT-only (200 mg/kg bw/day) and AZT-3TC (200 mg AZT + 100 mg 3TC/kg bw/day) groups at 13 days of age. These results suggest that the mutagenicity by these nucleoside analogs is driven by cumulative dose, and raises the question of whether AZT-3TC has greater mutagenic effects than AZT alone in perinatally exposed children. Environ. Mol. Mutagen. © 2007 Wiley-Liss, Inc.

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