PT  - JOURNAL ARTICLE
AU  - Shaojun Yang
AU  - Yi-Hua Jan
AU  - Vladimir Mishin
AU  - Jason R. Richardson
AU  - Muhammad M. Hossain
AU  - Ned D. Heindel
AU  - Diane E. Heck
AU  - Debra L. Laskin
AU  - Jeffrey D. Laskin
TI  - Sulfa Drugs Inhibit Sepiapterin Reduction and Chemical Redox Cycling by Sepiapterin Reductase
AID  - 10.1124/jpet.114.221572
DP  - 2015 Mar 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 529--540
VI  - 352
IP  - 3
4099  - http://jpet.aspetjournals.org/content/352/3/529.short
4100  - http://jpet.aspetjournals.org/content/352/3/529.full
SO  - J Pharmacol Exp Ther2015 Mar 01; 352
AB  - 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.