Oxidants from nicotinamide adenine dinucleotide phosphate oxidase are involved in triggering cell proliferation in the liver due to peroxisome proliferators | Academic Article individual record

It was shown that 4-chloro-6-(2,3-xylidino)-2-pyrimidinylthio acetic acid (Wy-14,643), a potent peroxisome proliferator, caused rapid oxidant-dependent activation of nuclear factor κB (NF-κB) in Kupffer cells in vivo and activated superoxide production by isolated Kupffer cells. Here, we tested the hypothesis that NADPH oxidase (NADPH OX) is the source of oxidants increased by Wy-14,643. Indeed, both activation of NF-κB and increases in cell proliferation due to a single dose of Wy-14,643 (100 mg/kg) were prevented completely when rats were pretreated with diphenyleneiodonium (1 mg/kg), an inhibitor of NADPH OX. p47(phox) is a critical subunit of NADPH OX; therefore, p47(phox) knockout mice were used to specifically address the hypothesis of NADPH OX involvement. In livers of wild-type mice, Wy-14,643 activated NF-κB, followed by an increase in mRNA for tumor necrosis factor α. Importantly, these changes did not occur in p47(phox) knockouts. Moreover, when Kupffer cells were treated with Wy-14,643 in vitro, superoxide production was increased in cells from wild-type but not p47(phox)-null mice. Finally, when mice were fed a Wy·14,643-containing (0.1%) diet for 7 days, the increase in liver weight and cell proliferation caused by Wy·14,643 in wild-type mice was blocked in p47(phox)-null mice. Combined, these results are consistent with the hypothesis that Wy-14,643 activates NADPH OX, which leads to NF-κB-mediated production of mitogens that causes hepatocellular proliferation characteristic of this class of nongenotoxic carcinogens.

author list (cited authors)
Rusyn, I., Yamashina, S., Segal, B. H., Schoonhoven, R., Holland, S. M., Cattley, R. C., Swenberg, J. A., & Thurman, R. G.
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  • NF-kappa B
  • Enzyme Inhibitors
  • RNA, Messenger
  • Cell Division
  • NADPH Oxidase
  • Mice, Knockout
  • Rats
  • Onium Compounds
  • Liver
  • Superoxides
  • Animals
  • Mice
  • Kupffer Cells
  • Pyrimidines
  • Tumor Necrosis Factor-alpha
  • Mice, Inbred C57BL
  • Rats, Sprague-Dawley
  • Peroxisome Proliferators
  • Carcinogens
  • Female
  • Phosphoproteins