Effect of tributyltin (TBT) on ATP levels in human natural killer (NK) cells: relationship to TBT-induced decreases in NK function

J Appl Toxicol. Jan-Feb 2007;27(1):86-94. doi: 10.1002/jat.1202.

Abstract

The purpose of this study was to investigate the role that tributyltin (TBT)-induced decreases in ATP levels may play in TBT-induced decreases in the tumor lysing (lytic) function of natural killer (NK) cells. NK cells are a subset of lymphocytes that act as an initial immune defense against tumor cells and virally infected cells. TBT is an environmental contaminant that has been detected in human blood, which has been shown to interfere with ATP synthesis. Previous studies have shown that TBT is able to decrease very significantly the lytic function of NK cells. In this study NK cells were exposed to various concentrations of TBT and to two other compounds that interfere with ATP synthesis (rotenone a complex I inhibitor and oligomycin an ATP synthase inhibitor) for various lengths of time before determining the levels of ATP and lytic function. Exposures of NK cells to 10, 25, 50 and 100 nm TBT did not significantly reduce ATP levels after 24 h. However, these same exposures caused significant decreases in cytotoxic function. Studies of brief 1 h exposures to a range of TBT, rotenone and oligomycin concentrations followed by 24 h, 48 h and 6 day periods in compound-free media prior to assaying for ATP levels or cytotoxic function showed that each of the compounds caused persistent decreases in ATP levels and lytic function of NK cells. Exposures to 0.05-5 microm rotenone or oligomycin for 1 h reduced ATP levels by 20-25% but did not have any measurable effect on the ability of NK cells to lyse tumor cells. ATP levels were also decreased by about 20-25% after 24 h or 48 h exposures to rotenone or oligomycin (0.5 microm ), and the lytic function was decreased by about 50%. The results suggest that TBT-induced decreases in ATP levels were not responsible for the loss of cytotoxic function seen at 1 h and 24 h. However, TBT-induced decreases of NK-ATP levels may be at least in part responsible for losses of NK-cytotoxic function seen after 48 h and 6 day exposures.

Publication types

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

MeSH terms

  • Adenosine Triphosphate / metabolism*
  • Antigens, CD / metabolism
  • Cell Survival / drug effects
  • Cytotoxicity, Immunologic / drug effects*
  • Dose-Response Relationship, Drug
  • Electron Transport Complex I / antagonists & inhibitors
  • Enzyme Inhibitors / pharmacology
  • Female
  • GPI-Linked Proteins
  • Humans
  • K562 Cells
  • Killer Cells, Natural / drug effects*
  • Killer Cells, Natural / immunology
  • Killer Cells, Natural / metabolism
  • Male
  • Mitochondrial Proton-Translocating ATPases / antagonists & inhibitors
  • Oligomycins / pharmacology
  • Receptors, IgG / metabolism
  • Rotenone / pharmacology
  • Time Factors
  • Trialkyltin Compounds / toxicity*
  • Water Pollutants, Chemical / toxicity*

Substances

  • Antigens, CD
  • Enzyme Inhibitors
  • FCGR3B protein, human
  • GPI-Linked Proteins
  • Oligomycins
  • Receptors, IgG
  • Trialkyltin Compounds
  • Water Pollutants, Chemical
  • Rotenone
  • tributyltin
  • Adenosine Triphosphate
  • Mitochondrial Proton-Translocating ATPases
  • Electron Transport Complex I