Oxidation of propylthiouracil to reactive metabolites by activated neutrophils. Implications for agranulocytosis.
Propylthiouracil (PTU) is associated with idiosyncratic agranulocytosis that may be due to reactive metabolites generated from oxidative metabolism by neutrophils. Therefore, the metabolism of PTU was investigated in activated neutrophils. Three oxidized metabolites were observed on HPLC: PTU-disulfide, propyluracil-2-sulfinate, and propyluracil-2-sulfonate (PTU-SO3-). No metabolism was detected in cells that had not been activated. Metabolism was inhibited by sodium azide and by catalase. The same products were produced by myeloperoxidase (MPO) in an MPO/H2O2/Cl- system. PTU inhibited its own metabolism; however, complete conversion to PTU-SO3- could be achieved with optimal PTU concentrations. MPO/H2O2 without Cl- produced only slight metabolism. The PTU-sulfenyl chloride is a postulated intermediate. In the absence of chloride, oxidation might proceed through propyluracil-2-sulfenic acid. The sulfenyl chloride and PTU-SO3- are both chemically reactive with sulfhydryl compounds such as N-acetylcysteine. Such reactive metabolites, generated by activated neutrophils, may be involved in hypersensitivity reactions associated with PTU, such as agranulocytosis.
Waldhauser
L
L
Faculty of Pharmacy, University of Toronto, Ontario.
Uetrecht
J
J
D000380:Agranulocytosis / Q000378:metabolism*; D001386:Azides / Q000494:pharmacology; D002374:Catalase / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid; D006801:Humans; D066298:In Vitro Techniques; D013058:Mass Spectrometry; D009504:Neutrophils / Q000378:metabolism*; D010084:Oxidation-Reduction; D011441:Propylthiouracil / Q000378:metabolism*; D019810:Sodium Azide; D013056:Spectrophotometry, Ultraviolet
D001386:Azides; D011441:Propylthiouracil; D019810:Sodium Azide; D002374:Catalase