Variability in interindividual genotoxic responses in normal human mammary epithelial (NHME) cells exposed to zidovudine.
Olivero-OA; Das-S; Whipkey-DL; Weston-A; Poirier-M
Environ Mutagen 2003 Jan; 41(3):196
The nucleoside analog Zidovudine (AZT), used as therapy for HIV-1, becomes phosphorylated and incorporated into DNA, acting as a DNA chain terminator The numerous genotoxic effects of AZT exposure have been described (IARC 7673-128, 2000). A high degree of variability has been observed in the extent of AZT incorporation into peripheral blood DNA of HIV-1- infected patients The underlying mechanisms for this variability are unknown, but insights might be gained from studies using normal cultured cells from many different individuals Here we explore the genotoxicity of AZT in 19 NHME cell strains obtained from reduction mammoplasty cultured for 6 passages before exposure to 0 or 200 uM AZT for 24 hr AZT -DNA incorporation was determined by radioimmunoassay using antisera specific for AZT incorporated into DNA Seven of the 19 cell strains did not have detectable levels of AZT -DNA (limit of detection = 5 AZT molecules/106 nucleotides) Eight out of 19 cell strains had AZT- DNA levels ranging from 6 to 50 AZT molecules/10(6) nucleotides Three cell strains had AZT -DNA levels ranging from 51 to 199 AZT molecules/10(6) nucleotides, and one cell strain had more than 200 molecules of AZT/10(6) nucleotides It is possible that the differences in AZT -DNA incorporation values reflect interindividual variability in intracellular AZT metabolism, but other more general factors may also contribute Studies are underway to examine the response of cell strains having differing AZT -DNA incorporation levels to the direct acting clastogen bleomycin. Cells are being examined for survival, formation of micronuclei, chromosomal aberrations, apoptosis and genomic instability In addition, the same cell strains will be subjected to analysis of polymorph isms in genes responsible for AZT phosphorylation.
Deoxyribonucleic-acids; Cellular-structures; Cellular-function; Cell-growth; Nucleotides; Chromosome-damage; Genotoxic-effects
Conference/Symposia Proceedings; Abstract
Research Tools and Approaches: Cancer Research Methods
Environmental Mutagenesis. Environmental Mutagen Society 34th Annual Meeting, May 10-14, 2003, Miami Beach, Florida