Human inter-individual variability in metabolism and genotoxic response to zidovudine.
Olivero-OA; Ming-JM; Das-S; Vazquez-IL; Richardson-DL; Weston-A; Poirier-MC
Toxicol Appl Pharmacol 2008 Apr; 228(2):158-164
A mainstay of the antiretroviral drugs used for therapy of HIV- 1, zidovudine (AZT) is genotoxic and becomes incorporated into DNA. Here we explored host inter-individual variability in AZT-DNA incorporation, by AZT radioimmunoassay (RIA), using 19 different strains of normal human mammary epithelial cells (NHMECs) exposed for 24 h to 200 mu M AZT. Twelve of the 19 NEMEC strains showed detectable AZT-DNA incorporation levels (16 to 259 molecules of AZT/10(6) nucleotides), while 7 NEMEC strains did not show detectable AZT-DNA incorporation. In order to explore the basis for this variability, we compared the 2 NEMEC strains that showed the highest levels of AZT-DNA incorporation (HI and H2) with 2 strains showing no detectable AZT-DNA incorporation (L1 and L2). All 4 strains had similar (>= 80%) cell survival, low levels of accumulation of cells in S-phase, and no relevant differences in response to the direct-acting mutagen bleomycin (BLM). Finally, when levels of thymidine kinase I (TK1), the first enzyme in the pathway for incorporation of AZT into DNA, were determined by Western blot analysis in all 19 NEMEC strains at 24 h of AZT exposure, higher TK1 protein levels were found in the 12 strains showing AZT-DNA incorporation, compared to the 7 showing no incorporation (p=0.0005, Mann-Whitney test). Furthermore, strains L1 and L2, which did not show AZT-DNA incorporation at 24 h, did have measurable incorporation by 48 and 72 h. These data suggest that variability in AZT-DNA incorporation may be modulated by inter-individual differences in the rate of induction of TK1 in response to AZT exposure.
Genes; Genetic-factors; Genotoxic-effects; Genotoxicity; Radiation-effects; Mutagenicity; Cell-alteration; Cell-biology; Cell-transformation; Molecular-biology; HIV; Diseases; Cell-cultures; Exposure-levels; Exposure-assessment; DNA-damage; Metabolism;
Author Keywords: AZT; Nucleoside analogs; Thymidine kinase 1
Ofelia A. Olivero, NCI, Lab Canc Biol & Genet, Carcinogen DNA Interact Sect, NIH, 37 Convent Dr MSC 4255,Bldg 37 Rm 4032B, Bethesda, MD 20892
Toxicology and Applied Pharmacology