TY - JOUR
T1 - Sustained formation of α-(4-pyridyl-1-oxide)-N-tert-butylnitrone radical adducts in mouse liver by peroxisome proliferators is dependent upon peroxisome proliferator-activated receptor-α, but not NADPH oxidase
AU - Woods, Courtney G.
AU - Burns, Amanda M.
AU - Maki, Akira
AU - Bradford, Blair U.
AU - Cunningham, Michael L.
AU - Connor, Henry D.
AU - Kadiiska, Maria B.
AU - Mason, Ronald P.
AU - Peters, Jeffrey M.
AU - Rusyn, Ivan
N1 - Funding Information:
Financial support for these studies was provided, in part, by grants from the National Institutes of Health (NIH): R01-ES12686, P30-ES10126, U19-ES11391, K22-ES11660, and F32-ES13342. We thank Dr. Wonyoung Tak with the University of North Carolina–Chapel Hill for providing assistance with mouse bile collection.
PY - 2007/2/1
Y1 - 2007/2/1
N2 - Reactive oxygen species are thought to be crucial for peroxisome proliferator-induced liver carcinogenesis. Free radicals have been shown to mediate the production of mitogenic cytokines by Kupffer cells and cause DNA damage in rodent liver. Previous in vivo experiments demonstrated that acute administration of the peroxisome proliferator di(2-ethylhexyl) phthalate (DEHP) led to an increase in production of α-(4-pyridyl-1-oxide)-N-tert-butylnitrone (POBN) radical adducts in liver, an event that was dependent on Kupffer cell NADPH oxidase, but not peroxisome proliferator-activated receptor (PPAR)α. Here, we hypothesized that continuous treatment with peroxisome proliferators will cause a sustained formation in POBN radical adducts in liver. Mice were fed diets containing either 4-chloro-6-(2,3-xylidino)-2-pyrimidinylthioacetic acid (WY-14,643, 0.05% w/w) or DEHP (0.6% w/w) for up to 3 weeks. Liver-derived radical production was assessed in bile samples by measuring POBN radical adducts using electron spin resonance. Our data indicate that WY-14,643 causes a sustained increase in POBN radical adducts in mouse liver and that this effect is greater than that of DEHP. To understand the molecular source of these radical species, NADPH oxidase-deficient (p47phox-null) and PPARα-null mice were examined after treatment with WY-14,643. No increase in radicals was observed in PPARα-null mice that were treated with WY-14,643 for 3 weeks, while the response in p47phox-nulls was similar to that of wild-type mice. These results show that PPARα, not NADPH oxidase, is critical for a sustained increase in POBN radical production caused by peroxisome proliferators in rodent liver. Therefore, peroxisome proliferator-induced POBN radical production in Kupffer cells may be limited to an acute response to these compounds in mouse liver.
AB - Reactive oxygen species are thought to be crucial for peroxisome proliferator-induced liver carcinogenesis. Free radicals have been shown to mediate the production of mitogenic cytokines by Kupffer cells and cause DNA damage in rodent liver. Previous in vivo experiments demonstrated that acute administration of the peroxisome proliferator di(2-ethylhexyl) phthalate (DEHP) led to an increase in production of α-(4-pyridyl-1-oxide)-N-tert-butylnitrone (POBN) radical adducts in liver, an event that was dependent on Kupffer cell NADPH oxidase, but not peroxisome proliferator-activated receptor (PPAR)α. Here, we hypothesized that continuous treatment with peroxisome proliferators will cause a sustained formation in POBN radical adducts in liver. Mice were fed diets containing either 4-chloro-6-(2,3-xylidino)-2-pyrimidinylthioacetic acid (WY-14,643, 0.05% w/w) or DEHP (0.6% w/w) for up to 3 weeks. Liver-derived radical production was assessed in bile samples by measuring POBN radical adducts using electron spin resonance. Our data indicate that WY-14,643 causes a sustained increase in POBN radical adducts in mouse liver and that this effect is greater than that of DEHP. To understand the molecular source of these radical species, NADPH oxidase-deficient (p47phox-null) and PPARα-null mice were examined after treatment with WY-14,643. No increase in radicals was observed in PPARα-null mice that were treated with WY-14,643 for 3 weeks, while the response in p47phox-nulls was similar to that of wild-type mice. These results show that PPARα, not NADPH oxidase, is critical for a sustained increase in POBN radical production caused by peroxisome proliferators in rodent liver. Therefore, peroxisome proliferator-induced POBN radical production in Kupffer cells may be limited to an acute response to these compounds in mouse liver.
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UR - http://www.scopus.com/inward/citedby.url?scp=33845925868&partnerID=8YFLogxK
U2 - 10.1016/j.freeradbiomed.2006.10.053
DO - 10.1016/j.freeradbiomed.2006.10.053
M3 - Article
C2 - 17210446
AN - SCOPUS:33845925868
SN - 0891-5849
VL - 42
SP - 335
EP - 342
JO - Free Radical Biology and Medicine
JF - Free Radical Biology and Medicine
IS - 3
ER -