N-chlorination of sulfamethoxazole and dapsone by the myeloperoxidase system.
It is known that activation of neutrophils or monocytes leads to the formation of hydrogen peroxide and the release of myeloperoxidase (MPO). We found that sulfamethoxazole was chlorinated by the combination of MPO, hydrogen peroxide, and chloride. The product, N-chlorosulfamethoxazole, is reasonably stable but reacts rapidly with a variety of compounds. The same product was formed by the reaction between sulfamethoxazole and hypochlorous acid, and dapsone was also N-chlorinated by the MPO system or hypochlorous acid. Although N-chlorination was not observed when sulfamethoxazole or dapsone was incubated with activated neutrophils, this is presumably because the chloramine products react rapidly with the cells. When radiolabeled sulfamethoxazole was incubated with activated neutrophils, covalent binding was observed. When radiolabeled sulfamethoxazole was incubated with MPO and hydrogen peroxide in the presence of albumin, covalent binding to the albumin occurred. Although binding to albumin occurred in the absence of chloride, it was increased by the presence of chloride. This suggests that N-chlorosulfamethoxazole may be one of several reactive metabolites of sulfamethoxazole that covalently bind to neutrophils. We suspect that covalent binding of arylamine drugs, such as sulfamethoxazole, to activated leukocytes is responsible for some of the adverse reactions associated with these drugs, especially adverse reactions that involve leukocytes such as agranulocytosis or drug-induced lupus.
Uetrecht
J P
JP
Faculty of Pharmacy, University of Toronto, Ontario, Canada.
Shear
N H
NH
Zahid
N
N
D002712:Chlorides / Q000378:metabolism*; D003622:Dapsone / Q000378:metabolism*; D006861:Hydrogen Peroxide / Q000378:metabolism / Q000494:pharmacology; D010084:Oxidation-Reduction; D009195:Peroxidase / Q000378:metabolism / Q000494:pharmacology*; D013420:Sulfamethoxazole / Q000378:metabolism*
D002712:Chlorides; D003622:Dapsone; D006861:Hydrogen Peroxide; D009195:Peroxidase; D013420:Sulfamethoxazole