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

Courtney G. Woods, Amanda M. Burns, Akira Maki, Blair U. Bradford, Michael L. Cunningham, Henry D. Connor, Maria B. Kadiiska, Ronald P. Mason, Jeffrey M. Peters, Ivan Rusyn

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)335-342
Number of pages8
JournalFree Radical Biology and Medicine
Volume42
Issue number3
DOIs
StatePublished - Feb 1 2007

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Peroxisome Proliferators
Peroxisome Proliferator-Activated Receptors
NADPH Oxidase
Liver
Oxides
Kupffer Cells
Rodentia
Electron Spin Resonance Spectroscopy
Nutrition
Bile
DNA Damage
Free Radicals
Paramagnetic resonance
Reactive Oxygen Species
Carcinogenesis
Cytokines
Diet
Acids
pirinixic acid
DNA

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Physiology (medical)

Cite this

Woods, Courtney G. ; Burns, Amanda M. ; Maki, Akira ; Bradford, Blair U. ; Cunningham, Michael L. ; Connor, Henry D. ; Kadiiska, Maria B. ; Mason, Ronald P. ; Peters, Jeffrey M. ; Rusyn, Ivan. / 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. In: Free Radical Biology and Medicine. 2007 ; Vol. 42, No. 3. pp. 335-342.
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abstract = "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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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. / Woods, Courtney G.; Burns, Amanda M.; Maki, Akira; Bradford, Blair U.; Cunningham, Michael L.; Connor, Henry D.; Kadiiska, Maria B.; Mason, Ronald P.; Peters, Jeffrey M.; Rusyn, Ivan.

In: Free Radical Biology and Medicine, Vol. 42, No. 3, 01.02.2007, p. 335-342.

Research output: Contribution to journalArticle

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AU - Burns, Amanda M.

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AU - Connor, Henry D.

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AU - Mason, Ronald P.

AU - Peters, Jeffrey M.

AU - Rusyn, Ivan

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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.

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