1. The antithyroid agent 6-n-propyl-2-thiouracil is a mechanism-based inactivator of the neuronal nitric oxide synthase isoform.
- Author
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Wolff DJ and Marks N
- Subjects
- Animals, Arginine pharmacology, Biopterins pharmacology, Calcium metabolism, Calmodulin pharmacology, Carbon Monoxide chemistry, Carbon Monoxide metabolism, Carbon Radioisotopes, Citrulline metabolism, Enzyme Activation drug effects, Enzyme Inhibitors pharmacology, Heme metabolism, Kinetics, Nitric Oxide metabolism, Nitric Oxide Synthase chemistry, Nitric Oxide Synthase metabolism, Nitric Oxide Synthase Type I, Pituitary Neoplasms drug therapy, Pituitary Neoplasms metabolism, Rats, Thiouracil pharmacokinetics, Thiouracil pharmacology, Tumor Cells, Cultured, Antithyroid Agents pharmacology, Biopterins analogs & derivatives, Nitric Oxide Synthase antagonists & inhibitors, Propylthiouracil pharmacology
- Abstract
6-n-Propyl-2-thiouracil (6-PTU), the antithyroid agent, produces a time-, concentration-, and turnover-dependent inactivation of the NO synthetic capability of the neuronal nitric oxide synthase isoform irreversible by either arginine or (6R)-5,6,7,8-tetrahydro-L-biopterin. By contrast 6-PTU produces an inhibition of the cytokine-inducible and endothelial nitric oxide synthases fully reversible by arginine. The inactivation of neuronal nitric oxide synthase by 6-PTU follows first order kinetics, and is inhibited competitively by both arginine and (6R)-5,6,7,8-tetrahydro-L-biopterin, but is not accompanied by either a loss of heme-CO binding, heme fluorescence, or disassembly of dimeric structure. 2-Thiouracil behaves qualitatively identically to 6-PTU. Turnover-dependent inactivation of neuronal nitric oxide synthase by [2-14C]-2-thiouracil is accompanied by incorporation of radioactivity into the polypeptide chain. Ca2+-dependent NO formation by GH3 pituitary cells is inhibited by 6-PTU in a manner enhanced by depletion of either extracellular arginine or intracellular (6R)-5,6,7,8-tetrahydro-L-biopterin. These observations establish that 6-PTU is an alternate substrate, mechanism-based inactivator of the neuronal nitric oxide synthase isoform with the ability to suppress cellular NO formation.
- Published
- 2002
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