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National Institute of Environmental Health Sciences

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Publication Detail

Title: Sulfa drugs inhibit sepiapterin reduction and chemical redox cycling by sepiapterin reductase.

Authors: Yang, Shaojun; Jan, Yi-Hua; Mishin, Vladimir; Richardson, Jason R; Hossain, Muhammad M; Heindel, Ned D; Heck, Diane E; Laskin, Debra L; Laskin, Jeffrey D

Published In J Pharmacol Exp Ther, (2015 Mar)

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.

PubMed ID: 25550200 Exiting the NIEHS site

MeSH Terms: Alcohol Oxidoreductases/antagonists & inhibitors*; Alcohol Oxidoreductases/chemistry; Alcohol Oxidoreductases/metabolism*; Animals; Humans; Mice; Oxidation-Reduction/drug effects; PC12 Cells; Protein Structure, Secondary; Pterins/antagonists & inhibitors*; Pterins/chemistry; Pterins/metabolism*; Rats; Sulfasalazine/pharmacology*; Sulfathiazole; Sulfathiazoles/pharmacology*

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