Procainamide hydroxylamine lymphocyte toxicity—I. Evidence for participation by hemoglobin

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

“…It is highly likely that this metabolite (or its further oxidation product, the nitroso compound) is responsible for many of the adverse effects associated with SPS. This is in agreement with the proposed mechanisms of toxicity of other sulphonamides (Reider et al, 1989;Shear & Spielberg, 1985), dapsone (Coleman etal., 1989;Uetrecht etal., 1988) and procainamide (Uetrecht, 1985); the hydroxylamines of the latter two compounds have, as with SPy-NOH in the present study, been shown to cause cytotoxicity (Coleman et al, 1989;Rubin et al, 1987) and methaemoglobin formation (Roberts et al, 1989;Tingle et al, 1990).…”

Autoimmunity caused by disruption of central T cell tolerance. A murine model of drug-induced lupus.

“…Therefore, global immune tolerance was preserved to the strong negativeselecting membrane self-antigens such as the minor lymphocyte-stimulating antigens that are expressed on the surface of splenic and thymic antigen presenting cells. Finally, since PAHA is cytotoxic to dividing cells in vitro under certain conditions (8,35,38), it is possible that intracellular macromolecules released from dying thymocytes could influence T cell selection. However, no increase in cell death was detected by exposure of thymi to PAHA ex vivo in the present studies.…”

“…We propose that transformation of circulating procainamide to PAHA, as demonstrated for neutrophils activated in vitro (10)(11)(12)(13), may occur in the thymus by in situ activated phagocytic cells during a localized inflammatory event. Although PAHA generated in vivo by this episodic mechanism is unlikely to be physically detectable because of the reactive nature and lability of this metabolite (7,8,35), nitroprocainamide, a stable further oxidative product of the hydroxylamine, has been reported in the urine of procainamide-treated rats and patients (15,36), and evidence for in vivo metabolism of procainamide to PAHA was obtained by the adoptive transfer popliteal lymph node assay (14). Although therapeutic steady-state plasma levels of procainamide are usually 15-40 M (37) and we used 4 mM PAHA in vivo, PAHA was introduced into a thymic lobe as a single bolus in 20 l, and we suspect that only a small proportion actually occupied thymic stroma.…”

Modulation of procainamide toxicity by selenium-enriched yeast in rats

“…One of the most important of these drugs is procainamide (Mongey and Hess 1989;Mongey et al 1992). Immunological and free radical processes are believed to be involved in the pathogenesis of lupus-like syndrome (Roberts et al 1989;Adams et al 1990;Uetrecht 1990). Recently, we have observed that administration of procainamide to rats caused an increase in antioxidant activity (Magner-Wr6bel et al 1993).…”