Metabolism of procainamide to a hydroxylamine by human neutrophils and mononuclear leukocytes.
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.
Uetrecht
J
J
Faculty of Pharmacy, University of Toronto, Ontario, Canada.
Zahid
N
N
Rubin
R
R
D001711:Biotransformation; D006801:Humans; D006898:Hydroxylamines / Q000097:blood*; D066298:In Vitro Techniques; D007700:Kinetics; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism*; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism*; D011342:Procainamide / Q000097:blood*; D011448:Prostaglandin Antagonists / Q000494:pharmacology
D006898:Hydroxylamines; D011448:Prostaglandin Antagonists; D011342:Procainamide