RESUMO
The drug procainamide (PA) is notorious for causing drug-induced systemic lupus erythematosus (SLE) in humans. Indirect evidence suggests that metabolism of PA to a reactive intermediate metabolite is involved in the pathogenesis of drug-induced SLE in that N-hydroxylation of the arylamine group of PA favors this condition, whereas N-acetylation prevents it. If this is correct, one would expect hydroxylamine-PA (HAPA) to be immunogenic, whereas N-acetyl-PA (N-ac-PA) should be nonimmunogenic. This hypothesis was confirmed by means of the popliteal lymph node assay (PLNA) in mice: injection of PA and N-ac-PA failed to induce a reaction in the direct PLNA, whereas HAPA induced a vigorous reaction. Using the adoptive transfer PLNA, splenic T cells of mice that had received three injections of HAPA were shown to be specifically sensitized to this metabolite, but not to PA or N-ac-PA. In this system, an anamnestic T cell response could also be elicited when homogenized peritoneal cells of mice that had been treated with PA for 4 months were used as the challenging antigen, indicating that the peritoneal cells of PA-treated animals contained or had been exposed to the reactive intermediate metabolite HAPA. Whereas in slow acetylator mice this 4-month PA treatment sufficed to generate HAPA in peritoneal cells, fast acetylators required additional stimulation of their oxidative metabolism in order to produce enough HAPA detectable by sensitized T cells. These findings clearly support the concept that reactive intermediate metabolites, such as HAPA, are generated by the oxidative metabolism of phagocytic cells and are immunogenic for T cells.
Assuntos
Acecainida/toxicidade , Linfonodos/efeitos dos fármacos , Procainamida/análogos & derivados , Procainamida/toxicidade , Linfócitos T/imunologia , Acecainida/imunologia , Acetilação , Animais , Feminino , Humanos , Hidroxilação , Memória Imunológica , Linfonodos/imunologia , Camundongos , Camundongos Endogâmicos A , Camundongos Endogâmicos C57BL , Cavidade Peritoneal/citologia , Fagócitos/metabolismo , Procainamida/imunologia , Procainamida/metabolismo , Baço/citologia , Linfócitos T/efeitos dos fármacosRESUMO
A number of lines of evidence suggest that the lupus-like symptoms associated with procainamide therapy may be caused by products of metabolic N-oxidation. In the present study, the perfusion of the isolated rat liver with a hemoglobin-free solution containing procainamide (100 microM) resulted in the rapid appearance of the N-oxidation metabolite procainamide hydroxylamine in the perfusate. Addition of procainamide hydroxylamine in vitro to whole rat blood (1-40 microM) resulted in a concentration-dependent loss of proliferative response among mononuclear cells isolated from the treated blood and cultured with mitogens (phytohemagglutinin, PHA-P: concanavalin A, Con A; and pokeweed mitogen, PWM), as well as a loss of viability. Similar effects on lymphocyte mitogen responsiveness were observed when procainamide hydroxylamine (1-40 microM) was added to rat whole splenic cell populations. Carbon monoxide or ascorbic acid pretreatment inhibited the toxicity of procainamide hydroxylamine to lymphocytes in whole blood, but only carbon monoxide pretreatment inhibited procainamide hydroxylamine-induced methemoglobin formation. These observations are consistent with the participation of hemoglobin in a redox cycle with procainamide hydroxylamine, generating products which are primarily responsible for its cytotoxicity in blood.
Assuntos
Hemoglobinas/fisiologia , Linfócitos/efeitos dos fármacos , Procainamida/análogos & derivados , Acecainida/toxicidade , Animais , Ácido Ascórbico/farmacologia , Monóxido de Carbono/farmacologia , Fenômenos Químicos , Química , Técnicas In Vitro , Fígado/efeitos dos fármacos , Masculino , Metemoglobina/biossíntese , Monócitos/efeitos dos fármacos , Monócitos/metabolismo , Procainamida/síntese química , Procainamida/toxicidade , Ratos , Ratos Endogâmicos , Baço/citologia , Baço/efeitos dos fármacos , Timidina/metabolismoRESUMO
Procainamide exerts vagolytic effects which are deleterious in clinical therapy for supraventricular arrhythmias. The purpose of the present study was to determine if N-acetylprocainamide (NAPA), an active metabolite of procainamide which has been proposed as an effective and less toxic alternative, would exert an equivalent degree of vagal blockade. In anesthetized dogs, the right cervical vagus nerve was electrically stimulated at supramaximal voltage using frequencies from 0.5 to 20 Hz to slow the sinus rate. The ability of NAPA and procainamide to block this response was tested with infusion of equimolar doses (1.0 and 0.87 mg/kg/min i.v., respectively) continuously over a period of 40-78 min. Both drugs exerted statistically significant vagolytic effects at the higher frequencies of stimulation. Although the vagolytic effect appeared to be more pronounced with procainamide, this could not be demonstrated by statistical analysis of the data.