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Oxidants from Nicotinamide Adenine Dinucleotide Phosphate Oxidase Are Involved in Triggering Cell Proliferation in the Liver Due to Peroxisome Proliferators¹

Laboratory of Hepatobiology and Toxicology, Department of Pharmacology [I. R., S. Y., R. G. T.], Curriculum in Toxicology [I. R., J. A. S., R. G. T.], and Department of Environmental Sciences and Engineering [R. S., J. A. S.], University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599; Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, Maryland 20892 [B. H. S., S. M. H.]; and Chemical Industry Institute of Toxicology, Research Triangle Park, North Carolina 27709 [R. C. C.].

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 B (NF-B) 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-B 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-B, followed by an increase in mRNA for tumor necrosis factor . 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-B-mediated production of mitogens that causes hepatocellular proliferation characteristic of this class of nongenotoxic carcinogens.

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