Human Inter-Individual Variability in Metabolism and Genotoxic Response to Zidovudine

Details

• Personal Author:
  Das S ; Ming JM ; Olivero OA ; Poirier MC ; Richardson DL ; Vazquez IL ; Weston A
• Description:
  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. [Description provided by NIOSH]
• Subjects:
  Cells, Cultured DNA Energy Metabolism Environmental Monitoring Genetics HIV Mutagens Occupational Health Radiation Safety
• Keywords:
  Author Keywords: AZT Cell-alteration Cell-biology Cell-cultures Cell-transformation Diseases DNA-damage Exposure-assessment Exposure-levels Genes Genetic-factors Genotoxic-effects Genotoxicity Metabolism Molecular-biology Mutagenicity Nucleoside Analogs Radiation-effects Thymidine Kinase 1

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• ISSN:
  0041-008X
• Document Type:
  Text
• Genre:
  Journal Article
• Place as Subject:
  Maryland ; OSHA Region 3 ; West Virginia
• CIO:
  National Institute for Occupational Safety and Health (NIOSH)
• Division:
  DRDS - Division of Respiratory Disease Studies
• Topic:
  Workplace Safety & Health
• Location:
  North America
• Pages in Document:
  158-164
• Volume:
  228
• Issue:
  2
• NIOSHTIC Number:
  nn:20033865
• Citation:
  Toxicol Appl Pharmacol 2008 Apr; 228(2):158-164
• Contact Point Address:
  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
• Email:
  oliveroo@exchange.nih.gov
• Federal Fiscal Year:
  2008
• Peer Reviewed:
  True
• Source Full Name:
  Toxicology and Applied Pharmacology
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:33523381f49d72326d55a2ffc48220473f82e756899b11b3a8547ddd5a404e059a8d1cacb298470e7a4cde8721d51386f7f84911f98aa96045381010d049a466
• Download URL:
  https://stacks.cdc.gov/view/cdc/189281/cdc_189281_DS1.pdf
• File Type:
  [PDF - 370.42 KB ]