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 auto immune syndrome resembling systemic lupus erythematosus. Adverse drug reactions, such as drug-induced lupus, often involve reactive intermed iates. Oxidation of hydralazine by liver microsomes or activated leuko cytes leads to reactive intermediates that covalently bind to protein and may be involved in hydralazine-induced lupus. Oxidation of hydrala zine to a reactive intermediate by cells involved in immune response, such as leukocytes, would be more likely to lead to an autoimmune reac tion, such as drug-induced lupus, than would oxidation by cells in the liver. Leukocytes possess a defense system that generates HOCl in res ponse to invading microorganisms. Hydralazine was oxidized to a reacti ve intermediate by HOCl generated by activated leukocytes. The reactiv e intermediate was trapped with N-acetylcysteine and the adduct was id entified as 1-phthalazylmercapturic acid. The reactive intermediate is likely the diazonium salt of hydralazine. Two stable products were fo rmed in the reaction, phthalazine and phthalazinone. Although phthalaz ine 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 th e putative diazonium salt with water. We propose that this reactive me tabolite is responsible for hydralazine-induced lupus.