Metabolism of procainamide to a hydroxylamine by human neutrophils and mononuclear leukocytes

Abstract

The chronic use of procainamide is associated with a high incidence of drug-induced lupus and also agranulocytosis. We have previously demonstrated that procainamide is metabolized in the liver to reactive hydroxylamine (PAHA) and nitroso (nitroso-PA) metabolites which covalently bind to protein and are toxic to lymphocytes. We proposed that these metabolites were responsible for the toxicities of procainamide. However, PAHA and nitroso-PA do not appear to escape the liver in significant concentrations. In this paper we describe the metabolism of procainamide to a reactive hydroxylamine by neutrophils and mononuclear leukocytes. Such metabolism only occurs if the cells have been stimulated to have a respiratory burst. These observations have obvious possible implications for the mechanism of procainamide-induced agranulocytosis (formation of a reactive metabolite by neutrophils) and procainamide-induced lupus (formation of a reactive metabolite by monocytes). The metabolism of drugs to reactive metabolites by monocytes may be a general mechanism for hypersensitivity reactions because monocytes play a key role in the processing of antigen and stimulation of antibody synthesis.

Procainamide, but notN-Acetylprocainamide, Induces Protein Free Radical Formation on Myeloperoxidase: A Potential Mechanism of Agranulocytosis

“…PA has previously been shown to form an N-hydroxylamine and N-chloro-PA when oxidzed by activated neutrophils or MPO/H 2 O 2 , and MPO/H 2 O 2 /Cl − , respectively (40,41). It was shown previously that approximately 20% of PA results in N-chloro-PA in the presence of MPO/H 2 O 2 /Cl − and PA at pH 6 (41).…”

Direct and metabolism‐dependent toxicity of sulphasalazine and its principal metabolites towards human erythrocytes and leucocytes.

“…For comparison, the half-life of dapsonehydroxylamine, a structurally related compound, was determined in the same manner with the samples being analysed by the h.p.l.c. method of Uetrecht et al (1988 10.7 ± 0.9%, and 14.5 + 3.6%, respectively) compared with control, i.e. in the presence of NADPH (2 mM) only, (10.4 ± 0.7%).…”

“…Moreover, dapsone which is structurally very similar to SPy, and has a similar sideeffect profile, also causes toxicity via its hydroxylamine metabolite (Coleman et al, 1989;Uetrecht et al, 1988).…”

Initiation of Autoimmunity by a Reactive Metabolite of a Lupus-Inducing Drug in the Thymus

“…Drug (5,6). PAHA can be detected after the perfusion of rat liver with procainamide in a blood-free environment (7).…”

“…Using procainamide as the prototype, we were the first to report that activated peripheral blood neutrophils have capacity to metabolize procainamide to PAHA (14); the role of the respiratory burst and degranulation events associated with neutrophil activation was confirmed (15) and analyzed in detail (16). Drug metabolism by neutrophils occurs in the extracellular environment, in which released myloperoxidase, acting with hydrogen peroxide produced upon neutrophil activation, enzymatically oxidizes copresent drugs (17).…”