REACTIVITY AND POSSIBLE SIGNIFICANCE OF HYDROXYLAMINE AND NITROSO METABOLITES OF PROCAINAMIDE

  • 1 January 1985
    • journal article
    • research article
    • Vol. 232  (2) , 420-425
Abstract
Procainamide is metabolized to a hydroxylamine. The reactivities of this hydroxylamine and of the closely related nitroso derivative toward biological molecules were investigated with the objective of exploring possible mechanisms of procainamide-induced lupus. The hydroxylamine of procainamide was found to bind covalently to rat microsomal protein to a much greater degree than did metabolic activation. The hydroxylamine was readily converted nonezymatically to the nitroso derivative, and reducing agents such as ascorbate and NADPH, which reduce the nitroso derivative to the hydroxylamine, blocked covalent binding. The nitroso derivative is apparently the reactive species for covalent binding. Glutathione was shown to block covalent binding of procainamide metabolites, and the nitroso derivative, but not the hydroxylamine which reacted rapidly with glutathione forming a sulfinamide derivative. The covalent binding of the nitroso derivative to microsomal protein appeared to involve groups, because it, like the glutathione adduct, was readily cleaved by mild acid. The nature of the covalent binding to albumin and histone protein appeared different from that to microsomal protein in that most of the binding was stable to mild acid. The reactivity toward DNA was much less than that to protein. The observation that both the reactivity of nitrosoprocainamide and the specificity of antinuclear antibodies in procainamide-induced lupus are to histone protein rather than the DNA supports the hypothesis that this reactive metabolite plays a role in the etiology of procainamide induced lupus.