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Research ArticleToxicology

Sulfa Drugs Inhibit Sepiapterin Reduction and Chemical Redox Cycling by Sepiapterin Reductase

Shaojun Yang, Yi-Hua Jan, Vladimir Mishin, Jason R. Richardson, Muhammad M. Hossain, Ned D. Heindel, Diane E. Heck, Debra L. Laskin and Jeffrey D. Laskin
Journal of Pharmacology and Experimental Therapeutics March 2015, 352 (3) 529-540; DOI: https://doi.org/10.1124/jpet.114.221572
Shaojun Yang
Department of Environmental and Occupational Medicine, Rutgers Robert Wood Johnson Medical School (S.Y., Y.-H.J., J.R.R., M.H.H., J.D.L.) and Department of Pharmacology and Toxicology, Rutgers University, Piscataway, New Jersey (V.M., D.L.L.); Department of Chemistry, Lehigh University, Bethlehem, Pennsylvania (N.D.H.); and Department of Environmental Health Science, New York Medical College, Valhalla, New York (D.E.H.)
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Yi-Hua Jan
Department of Environmental and Occupational Medicine, Rutgers Robert Wood Johnson Medical School (S.Y., Y.-H.J., J.R.R., M.H.H., J.D.L.) and Department of Pharmacology and Toxicology, Rutgers University, Piscataway, New Jersey (V.M., D.L.L.); Department of Chemistry, Lehigh University, Bethlehem, Pennsylvania (N.D.H.); and Department of Environmental Health Science, New York Medical College, Valhalla, New York (D.E.H.)
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Vladimir Mishin
Department of Environmental and Occupational Medicine, Rutgers Robert Wood Johnson Medical School (S.Y., Y.-H.J., J.R.R., M.H.H., J.D.L.) and Department of Pharmacology and Toxicology, Rutgers University, Piscataway, New Jersey (V.M., D.L.L.); Department of Chemistry, Lehigh University, Bethlehem, Pennsylvania (N.D.H.); and Department of Environmental Health Science, New York Medical College, Valhalla, New York (D.E.H.)
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Jason R. Richardson
Department of Environmental and Occupational Medicine, Rutgers Robert Wood Johnson Medical School (S.Y., Y.-H.J., J.R.R., M.H.H., J.D.L.) and Department of Pharmacology and Toxicology, Rutgers University, Piscataway, New Jersey (V.M., D.L.L.); Department of Chemistry, Lehigh University, Bethlehem, Pennsylvania (N.D.H.); and Department of Environmental Health Science, New York Medical College, Valhalla, New York (D.E.H.)
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Muhammad M. Hossain
Department of Environmental and Occupational Medicine, Rutgers Robert Wood Johnson Medical School (S.Y., Y.-H.J., J.R.R., M.H.H., J.D.L.) and Department of Pharmacology and Toxicology, Rutgers University, Piscataway, New Jersey (V.M., D.L.L.); Department of Chemistry, Lehigh University, Bethlehem, Pennsylvania (N.D.H.); and Department of Environmental Health Science, New York Medical College, Valhalla, New York (D.E.H.)
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Ned D. Heindel
Department of Environmental and Occupational Medicine, Rutgers Robert Wood Johnson Medical School (S.Y., Y.-H.J., J.R.R., M.H.H., J.D.L.) and Department of Pharmacology and Toxicology, Rutgers University, Piscataway, New Jersey (V.M., D.L.L.); Department of Chemistry, Lehigh University, Bethlehem, Pennsylvania (N.D.H.); and Department of Environmental Health Science, New York Medical College, Valhalla, New York (D.E.H.)
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Diane E. Heck
Department of Environmental and Occupational Medicine, Rutgers Robert Wood Johnson Medical School (S.Y., Y.-H.J., J.R.R., M.H.H., J.D.L.) and Department of Pharmacology and Toxicology, Rutgers University, Piscataway, New Jersey (V.M., D.L.L.); Department of Chemistry, Lehigh University, Bethlehem, Pennsylvania (N.D.H.); and Department of Environmental Health Science, New York Medical College, Valhalla, New York (D.E.H.)
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Debra L. Laskin
Department of Environmental and Occupational Medicine, Rutgers Robert Wood Johnson Medical School (S.Y., Y.-H.J., J.R.R., M.H.H., J.D.L.) and Department of Pharmacology and Toxicology, Rutgers University, Piscataway, New Jersey (V.M., D.L.L.); Department of Chemistry, Lehigh University, Bethlehem, Pennsylvania (N.D.H.); and Department of Environmental Health Science, New York Medical College, Valhalla, New York (D.E.H.)
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Jeffrey D. Laskin
Department of Environmental and Occupational Medicine, Rutgers Robert Wood Johnson Medical School (S.Y., Y.-H.J., J.R.R., M.H.H., J.D.L.) and Department of Pharmacology and Toxicology, Rutgers University, Piscataway, New Jersey (V.M., D.L.L.); Department of Chemistry, Lehigh University, Bethlehem, Pennsylvania (N.D.H.); and Department of Environmental Health Science, New York Medical College, Valhalla, New York (D.E.H.)
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Abstract

Sepiapterin reductase (SPR) catalyzes the reduction of sepiapterin to dihydrobiopterin (BH2), the precursor for tetrahydrobiopterin (BH4), a cofactor critical for nitric oxide biosynthesis and alkylglycerol and aromatic amino acid metabolism. SPR also mediates chemical redox cycling, catalyzing one-electron reduction of redox-active chemicals, including quinones and bipyridinium herbicides (e.g., menadione, 9,10-phenanthrenequinone, and diquat); rapid reaction of the reduced radicals with molecular oxygen generates reactive oxygen species (ROS). Using recombinant human SPR, sulfonamide- and sulfonylurea-based sulfa drugs were found to be potent noncompetitive inhibitors of both sepiapterin reduction and redox cycling. The most potent inhibitors of sepiapterin reduction (IC50s = 31–180 nM) were sulfasalazine, sulfathiazole, sulfapyridine, sulfamethoxazole, and chlorpropamide. Higher concentrations of the sulfa drugs (IC50s = 0.37–19.4 μM) were required to inhibit redox cycling, presumably because of distinct mechanisms of sepiapterin reduction and redox cycling. In PC12 cells, which generate catecholamine and monoamine neurotransmitters via BH4-dependent amino acid hydroxylases, sulfa drugs inhibited both BH2/BH4 biosynthesis and redox cycling mediated by SPR. Inhibition of BH2/BH4 resulted in decreased production of dopamine and dopamine metabolites, 3,4-dihydroxyphenylacetic acid and homovanillic acid, and 5-hydroxytryptamine. Sulfathiazole (200 μM) markedly suppressed neurotransmitter production, an effect reversed by BH4. These data suggest that SPR and BH4-dependent enzymes, are “off-targets” of sulfa drugs, which may underlie their untoward effects. The ability of the sulfa drugs to inhibit redox cycling may ameliorate ROS-mediated toxicity generated by redox active drugs and chemicals, contributing to their anti-inflammatory activity.

Footnotes

    • Received November 21, 2014.
    • Accepted December 29, 2014.
  • This work was supported by the National Institutes of Health National Institute of Arthritis and Musculoskeletal and Skin Diseases [Grant U54-AR055073]; the National Institutes of Health National Institute of Neurological Disorders and Stroke [Grant U01-NS079249]; the National Institutes of Health National Cancer Institute [Grant R01-CA132624]; and the National Institutes of Health National Institute of Environmental Health Sciences [Grants R01-ES004738, R01-ES021800, and P30-ES005022].

  • dx.doi.org/10.1124/jpet.114.221572.

  • Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 352 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 352, Issue 3
1 Mar 2015
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Research ArticleToxicology

Sulfa Drugs Inhibit SPR

Shaojun Yang, Yi-Hua Jan, Vladimir Mishin, Jason R. Richardson, Muhammad M. Hossain, Ned D. Heindel, Diane E. Heck, Debra L. Laskin and Jeffrey D. Laskin
Journal of Pharmacology and Experimental Therapeutics March 1, 2015, 352 (3) 529-540; DOI: https://doi.org/10.1124/jpet.114.221572

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Research ArticleToxicology

Sulfa Drugs Inhibit SPR

Shaojun Yang, Yi-Hua Jan, Vladimir Mishin, Jason R. Richardson, Muhammad M. Hossain, Ned D. Heindel, Diane E. Heck, Debra L. Laskin and Jeffrey D. Laskin
Journal of Pharmacology and Experimental Therapeutics March 1, 2015, 352 (3) 529-540; DOI: https://doi.org/10.1124/jpet.114.221572
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