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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
Author(s) -
Torres Salina M.,
Walker Dale M.,
Carter Meghan M.,
Cook Dennis L.,
McCash Consuelo L.,
Cordova Edmund M.,
Olivero Ofelia A.,
Poirier Miriam C.,
Walker Ver E.
Publication year - 2007
Publication title -
environmental and molecular mutagenesis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1
H-Index - 87
eISSN - 1098-2280
pISSN - 0893-6692
DOI - 10.1002/em.20264
Subject(s) - zidovudine , hypoxanthine guanine phosphoribosyltransferase , abacavir , lamivudine , lymphoblast , thymidine kinase , pharmacology , virology , biology , cell culture , mutant , virus , biochemistry , hepatitis b virus , viral disease , genetics , herpes simplex virus , gene
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.