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. Apr-May 2007;48(3-4):224-38. doi: 10.1002/em.20264.

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 microM), 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 microM, 3 days), or to peak plasma-equivalent levels of AZT-3TC for an extended period (10 microM, 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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Anti-HIV Agents / toxicity
  • Cell Line
  • Cell Survival / drug effects
  • DNA / metabolism
  • Dideoxynucleosides / toxicity*
  • Drug Interactions
  • Female
  • Humans
  • Hypoxanthine Phosphoribosyltransferase / genetics
  • Lamivudine / toxicity*
  • Lymphocytes / drug effects
  • Lymphocytes / metabolism
  • Male
  • Maternal-Fetal Exchange
  • Mice
  • Mice, Inbred Strains
  • Mutagens / toxicity*
  • Mutation
  • Pregnancy
  • Reverse Transcriptase Inhibitors / toxicity*
  • Thymidine Kinase / genetics
  • Zidovudine / toxicity*

Substances

  • Anti-HIV Agents
  • Dideoxynucleosides
  • Mutagens
  • Reverse Transcriptase Inhibitors
  • Lamivudine
  • Zidovudine
  • DNA
  • Hypoxanthine Phosphoribosyltransferase
  • Thymidine Kinase
  • abacavir