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Molecular Pharmacology

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Research ArticleArticle

Phthalates Rapidly Increase Production of Reactive Oxygen Species in Vivo: Role of Kupffer Cells

Ivan Rusyn, Maria B. Kadiiska, Anna Dikalova, Hiroshi Kono, Ming Yin, Koichiro Tsuchiya, Ronald P. Mason, Jeffrey M. Peters, Frank J. Gonzalez, Brahm H. Segal, Steven M. Holland and Ronald G. Thurman
Molecular Pharmacology April 2001, 59 (4) 744-750; DOI: https://doi.org/10.1124/mol.59.4.744
Ivan Rusyn
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Maria B. Kadiiska
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Anna Dikalova
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Hiroshi Kono
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Ming Yin
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Koichiro Tsuchiya
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Ronald P. Mason
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Jeffrey M. Peters
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Frank J. Gonzalez
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Brahm H. Segal
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Steven M. Holland
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Ronald G. Thurman
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Abstract

The role of oxidants in the mechanism of tumor promotion by peroxisome proliferators remains controversial. The idea that induction of acyl-coenzyme A oxidase leads to increased production of H2O2, which damages DNA, seems unlikely; still, free radicals might be important in signaling in specialized cell types such as Kupffer cells, which produce mitogens. Because hard evidence for increased oxidant production in vivo after treatment with peroxisome proliferators is lacking, the spin-trapping technique and electron spin resonance spectroscopy were used. Rats were given di(2-ethylhexyl) phthalate (DEHP) acutely. The spin trapping agent α-(4-pyridyl-1-oxide)-N-tert-butylnitrone was also given and bile samples were collected for 4 h. Under these conditions, the intensity of the six-line radical adduct signal increased to a maximum value of 2.5-fold 2 h after administration of DEHP, before peroxisomal oxidases were induced. Furthermore, DEHP given with [13C2]dimethyl sulfoxide produced a 12-line electron spin resonance spectrum, providing evidence that DEHP stimulates ⋅OH radical formation in vivo. Furthermore, when rats were pretreated with dietary glycine, which inactivates Kupffer cells, DEHP did not increase radical signals. Moreover, similar treatments were performed in knockout mice deficient in NADPH oxidase (p47phox subunit). Importantly, DEHP increased oxidant production in wild-type but not in NADPH oxidase-deficient mice. These data provide evidence for the hypothesis that the molecular source of free radicals induced by peroxisome proliferators is NADPH oxidase in Kupffer cells. On the contrary, radical adduct formation was not affected in peroxisome proliferator-activated receptor α knockout mice. These observations represent the first direct, in vivo evidence that phthalates increase free radicals in liver before peroxisomal oxidases are induced.

Footnotes

    • Received September 21, 2000.
    • Accepted December 21, 2000.
  • Send reprint requests to: Ivan Rusyn, M.D., Ph.D., 1124 M.E. Jones Bldg., CB #7365, Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7365. E-mail:iir{at}med.unc.edu

  • This study was supported in part by National Institutes of Health Grants ES04325 and ES07126.

  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 59 (4)
Molecular Pharmacology
Vol. 59, Issue 4
1 Apr 2001
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Research ArticleArticle

Phthalates Rapidly Increase Production of Reactive Oxygen Species in Vivo: Role of Kupffer Cells

Ivan Rusyn, Maria B. Kadiiska, Anna Dikalova, Hiroshi Kono, Ming Yin, Koichiro Tsuchiya, Ronald P. Mason, Jeffrey M. Peters, Frank J. Gonzalez, Brahm H. Segal, Steven M. Holland and Ronald G. Thurman
Molecular Pharmacology April 1, 2001, 59 (4) 744-750; DOI: https://doi.org/10.1124/mol.59.4.744

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Research ArticleArticle

Phthalates Rapidly Increase Production of Reactive Oxygen Species in Vivo: Role of Kupffer Cells

Ivan Rusyn, Maria B. Kadiiska, Anna Dikalova, Hiroshi Kono, Ming Yin, Koichiro Tsuchiya, Ronald P. Mason, Jeffrey M. Peters, Frank J. Gonzalez, Brahm H. Segal, Steven M. Holland and Ronald G. Thurman
Molecular Pharmacology April 1, 2001, 59 (4) 744-750; DOI: https://doi.org/10.1124/mol.59.4.744
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