Reactive intermediates in the oxidation of hydralazine by HOCl: the major oxidant generated by neutrophils.
The use of the antihypertensive hydralazine is associated with an autoimmune syndrome resembling systemic lupus erythematosus. Adverse drug reactions, such as drug-induced lupus, often involve reactive intermediates. Oxidation of hydralazine by liver microsomes or activated leukocytes leads to reactive intermediates that covalently bind to protein and may be involved in hydralazine-induced lupus. Oxidation of hydralazine to a reactive intermediate by cells involved in immune response, such as leukocytes, would be more likely to lead to an autoimmune reaction, such as drug-induced lupus, than would oxidation by cells in the liver. Leukocytes possess a defense system that generates HOCl in response to invading microorganisms. Hydralazine was oxidized to a reactive intermediate by HOCl generated by activated leukocytes. The reactive intermediate was trapped with N-acetylcysteine and the adduct was identified as 1-phthalazylmercapturic acid. The reactive intermediate is likely the diazonium salt of hydralazine. Two stable products were formed in the reaction, phthalazine and phthalazinone. Although phthalazine is oxidized to phthalazinone by HOCl, the rate of the reaction is much too slow to explain the rapid production of phthalazinone. It is more likely that most of the phthalazinone is formed by reaction of the putative diazonium salt with water. We propose that this reactive metabolite is responsible for hydralazine-induced lupus.
Hofstra
A H
AH
Faculty of Pharmacy, University of Toronto, Ontario, Canada.
Uetrecht
J P
JP
D002851:Chromatography, High Pressure Liquid; D006830:Hydralazine / Q000737:chemistry*; D006997:Hypochlorous Acid / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D009504:Neutrophils / Q000378:metabolism; D010084:Oxidation-Reduction; D013056:Spectrophotometry, Ultraviolet
D006830:Hydralazine; D006997:Hypochlorous Acid