Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0024141 (systemic lupus erythematosus)
 44,322 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A/J mice are proposed as a model of the human lupus diathesis since we previously determined that they express a slow acetyltor phenotype while others showed them to have a predisposition to develop spontaneous and drug-induced antinuclear antibodies. A/J mice were mated with C57BL/6J mice, a rapid acetylator phenotype which is relatively resistant to spontaneous and drug-induced antinuclear antibodies, to assess the importance of slow acetylator status as a component of the lupus diathesis. Procainamide, a potent inducer of antinuclear antibodies, was acetylated to a lesser degree by A/J mice than by C57BL/6J mice. This difference, detectable by in vitro assay but not by urinary levels of acetylated drug, represents a genetic polymorphism which can be detected in F2 and backcross progency of these two strains. We confirmed that A/J mice have a higher incidence of spontaneous antinuclear antibodies than C57BL/6J mice and that in A/J mice these antibodies can be induced by oral procainamide (6 g/l of drinking water for 37 weeks); procainamide tended to suppress antinuclear antibody formation in C57BL/6J mice, however. Rapid and slow acetylators among F2 and backcross populations were identified by a test for N-acetyltransferase activity in blood hemolysates. These two groups together with their respective rapid and slow acetylator parents were compared in respect to incidence of antinuclear antibodies. Slow acetylator phenotypes among F2 and backcross mice were predisposed to high titers of antinuclear antibodies like the slow acetyltor A/J strain. However, long-term exposure to procainamide suppressed antinuclear antibody formation as was found in the rapid acetylator C57BL/6J strain. Thus, the ability to N-acetylate procainamide is not the sole factor controlling the ability of this drug to induce antinuclear antibodies.
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PMID:Antinuclear antibodies related to acetylator phenotype in mice. 697 Aug 9

In summary, procainamide is a useful agent for suppressing premature depolarization frequency. Its short half-life of elimination requires a dosing frequency of every 3 hours with regular dosage forms or every 6-8 hours with a sustained action dosage. Because of the extreme unpredictability of plasma concentration, the dosage must be titrated in each patient with electrocardiographic monitoring serving as the most useful method of evaluating efficacy. Maximum and minimum plasma concentrations are helpful in monitoring the achievement of therapeutic plasma levels and adjusting the frequency of dosing, especially in the presence of impaired renal function or low cardiac output. Adverse effects of procainamide include anorexia, nausea, vomiting, fatigue, insomnia, visual hallucinations, and disorientation; these are minor and cease with discontinuation of the drug. Agranulocytosis has rarely been reported. Long-term treatment has resulted in the occurrence of a lupus-like syndrome that is reversible when the drug is stopped. Procainamide is excreted in breast milk and infants of mothers receiving procainamide should not be nursed.
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PMID:Pharmacokinetics of a sustained release procainamide preparation. 703 27

Procainamide remains one of the most widely used antiarrhythmic agents in clinical practice. Currently, it is widely used alone or in combination with class I agents (eg, mexiletine or tocainide) to prevent recurrent ventricular tachycardia or symptomatic nonsustained ventricular tachycardia. Procainamide is also used for short-term treatment of ventricular tachycardia and a variety of supraventricular tachycardias, primarily atrial flutter and atrial fibrillation. Long-term procainamide therapy is limited by a number of systemic side effects, primarily lupus-like syndrome, gastrointestinal disturbances, and autoimmune blood dyscrasias. Procainamide levels can be useful in initial dose titrations; however, QRS and QT interval measurements help prevent drug toxicity. It is recommended that patients being started on antiarrhythmic therapy with procainamide be admitted to the hospital for monitoring to ensure that their QT interval is not excessively prolonged.
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PMID:Procainamide: a perspective on its value and danger. 813 53

Procainamide (PA) is the drug most commonly associated with the induction of autoantibodies and drug-related lupus (DRL). While the majority of these patients express autoantibodies, antibodies to the parent drug and metabolites, PA-hydroxylamine (PAHA) or nitroso-PA (NOPA), have not been reported in humans. Hapten-carrier conjugates were prepared using human hemoglobin (HgB) or autologous rabbit erythrocytes with PAHA or NOPA. PA was conjugated to rabbit serum albumin (RSA) or egg albumin (OVA) via diazotization and condensation methods. Rabbits were immunized with hapten conjugates in Freund's adjuvant. These hapten-carrier compounds (5-10 micrograms/ml) were used as test antigens for antibodies in sera from the rabbits and 40 patients on chronic PA treatment. 10 SLE patients, 33 elderly and 20 young normal controls by ELISA. Type I and II collagens were also used as test antigens for human sera. Sera from rabbits immunized with the PA compounds had elevated IgG antibody values to PA, PAHA and NOPA, but no autoantibodies. Absorption of the rabbit sera with the PA compounds reduced the antibody levels; ssDNA and histones failed to inhibit the total binding values. Mean binding to PA-OVA was 0.95 +/- 0.41 for PA patients and 1.37 +/- 0.26 standard error of means (S.E.M.) in the SLE patients compared to 0.37 +/- 0.14 S.E.M. in the normal sera (P < or = 0.05); similar binding values to PAHA-HgB and NOPA-HgB were also observed. Sixty-eight percent of the PA patients had antibodies to type II collagen. Elevated binding values to PA compounds were inhibited by absorption of human sera with ssDNA or total histones; absorption with PA or PAHA had no significant effect. These findings suggest that sera from PA patients containing high titers of autoantibodies cross-react in vitro with unrelated antigens.
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PMID:Study of procainamide hapten-specific antibodies in rabbits and humans. 825 39

A 70-year-old physician was admitted to our hospital because of bilateral pleural effusion and left-sided chest pain on deep inspiration. On admission, the APTT was prolonged and was not corrected with a 1:1 mixture of normal plasma. Results of serological examinations included a positive lupus-anticoagulant test and a positive ANA test at a titer of 1:1,280 in a homogeneous pattern. The patient's age, sex, symptoms, signs, and laboratory results all argued against the diagnosis of SLE except for ANA and lupus anticoagulant test. Because procainamide had been prescribed (250 mg every 6 h) for premature ventricular contractions for eight years before admission, procainamide-induced lupus was suspected. Procainamide was discontinued. Chest pain persisted and tests for c-reactive protein were positive. Prednisolone was administered. Procainamide induced lupus was diagnosed, because anti-histone H 2 A-H 2 B complex antibodies were high by enzyme-linked immunosorbent assay, and IgM-class anti-histone antibodies were found in response to H1, H 2 B and H 2 A-H 2 B complex (immunoblotting), which suggested the drug induced lupus. There are only a few reports of drug induced lupus in which the lupus-anticoagulant test was positive and prednisolone was indicated. The measurements of anti-histone antibodies and of expression of anti-histone antibodies were useful in distinguishing drug-induced lupus from SLE.
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PMID:[Procainamide-induced lupus in a patient with bilateral pleural effusion]. 975 5

Procainamide (PA) may cause drug-induced lupus, and its reactive metabolites, hydroxylamine-PA (HAPA) and nitroso-PA, are held responsible for this. Here, we show that N-oxidation of PA to these metabolites can take place in macrophages and lead to formation of neoantigens that sensitize T cells. Murine peritoneal macrophages (PMvarphi), exposed to PA in vitro, generated neoantigens related to HAPA as indicated by (1) their capacity to elicit a specific recall response of HAPA-primed T cells in the adoptive transfer popliteal lymph node (PLN) assay and (2) the appearance of metabolite-bound protein in PA-pulsed PMvarphi, as determined by Western blot. Analysis of five phase I enzymes that might be responsible for HAPA formation by PMvarphi pointed to prostaglandin H synthase-2 (PGHS-2) as a likely candidate. Experimental evidence that PA can be oxidized to HAPA by PGHS was obtained by exposing PA to PGHS in vitro. The resulting metabolites were identified by mass spectral analysis and covalent protein binding in ELISA. In vitro, PA exposure of PMvarphi of slow acetylator A/J and fast acetylator C57BL/6 mice failed to show significant strain differences in enzyme mRNA expression, enzyme activities, or formation of HAPA-related neoantigens. By contrast, after long-term PA treatment in vivo only in slow acetylators the PMvarphi harbored HAPA-related neoantigens and T cells were sensitized to them. PMvarphi of fast acetylator C57BL/6 mice only contained HAPA-related neoantigens, and their T cells were only sensitized to them if, in addition to long-term PA treatment, their donors had received injections of phorbol myristate acetate (PMA), a known enhancer of oxidative enzymes in phagocytes. In conclusion, PA treatment leads to N-oxidation of PA by enzymes, in particular PGHS-2, present in antigen-presenting cells (APC) and, hence, to generation of neoantigens which sensitize T cells. The enhanced neoantigen formation and T cell sensitization seen in slow acetylators might be explained by their higher concentration of PA substrate that is available for extrahepatic N-oxidation in APC.
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PMID:Procainamide, a drug causing lupus, induces prostaglandin H synthase-2 and formation of T cell-sensitizing drug metabolites in mouse macrophages. 1036 11

DNA methylation plays an essential role in maintaining cellular function, and changes in methylation patterns may contribute to the development of autoimmunity, aging and cancer. Evidence for a role in autoimmunity comes from studies demonstrating that inhibiting T lymphocyte DNA methylation causes autoreactivity in vitro and a lupus-like disease in vivo. The autoimmunity is due in part to the heterodimeric beta(2) integrin lymphocyte function-associated antigen-1 (LFA-1) (CD11a/CD18) overexpression, and T lymphocytes from lupus patients hypomethylate the same CD11a promoter sequences, overexpress LFA-1 and demonstrate the same autoreactivity. Procainamide and hydralazine, two drugs that cause a lupus-like disease, also inhibit T cell DNA methylation, increase LFA-1 expression and induce autoreactivity in vitro and autoimmunity in vivo, supporting the association of DNA hypomethylation and autoimmunity. Methylation patterns also change with age in T lymphocytes as well as other tissues, typically with an overall decrease in methylcytosine content, but with increases in some cytosine guanine dinucleotide (CpG) islands. Age-dependent hypomethylation contributes to LFA-1 overexpression with aging, which may play a role in the development of autoimmunity in the elderly and age-dependent methylation of CpG islands in the promoters of tumor suppressor genes is an early event in the development of some cancers. DNA hypomethylation also may contribute to carcinogenesis by promoting overexpression of proto-oncogenes, chromosomal translocations and loss of imprinting. The mechanisms causing altered DNA methylation in autoimmunity, aging and carcinogenesis are incompletely characterized but include exposure to environmental agents and drugs, diet, altered signaling in pathways regulating DNA methyltransferase expression and changes in endogenous regulatory mechanisms. Other mechanisms are likely to be identified as well.
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PMID:Role of DNA methylation in the regulation of cell function: autoimmunity, aging and cancer. 1216

Exposing genetically predisposed individuals to certain environmental agents is believed to cause human lupus. How environmental agents interact with the host to cause lupus is poorly understood. Procainamide and hydralazine are drugs that cause lupus in genetically predisposed individuals. Understanding how these environmental agents cause lupus may indicate mechanisms relevant to the idiopathic disease. Abnormal T cell DNA methylation, a repressive epigenetic DNA modification, is implicated in procainamide and hydralazine induced lupus, as well as idiopathic lupus. Procainamide is a competitive DNA methyltransferase (Dnmt) inhibitor, hydralazine inhibits ERK pathway signaling thereby decreasing Dnmt expression, and in lupus T cells decreased ERK pathway signaling causing a similar Dnmt decrease. T cells treated with procainamide, hydralazine, and other Dnmt and ERK pathway inhibitors cause lupus in mice. Whether the same genetic regulatory elements demethylate in T cells treated with Dnmt inhibitors, ERK pathway inhibitors, and in human lupus is unknown. CD70 (TNFSF7) is a B cell costimulatory molecule overexpressed on CD4(+) lupus T cells as well as procainamide and hydralazine treated T cells, and contributes to excessive B cell stimulation in vitro and in lupus. In this report we identify a genetic element that suppresses CD70 expression when methylated, and which demethylates in lupus and in T cells treated with Dnmt and ERK pathway inhibitors including procainamide and hydralazine. The results support a model in which demethylation of specific genetic elements in T cells, caused by decreasing Dnmt expression or inhibiting its function, contributes to drug-induced and idiopathic lupus through altered gene expression.
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PMID:Demethylation of the same promoter sequence increases CD70 expression in lupus T cells and T cells treated with lupus-inducing drugs. 1587 18

Procainamide, a type I antiarrhythmic agent, is used to treat a variety of atrial and ventricular dysrhythmias. It was reported that long-term therapy with procainamide may cause lupus erythematosus in 25-30% of patients. Interestingly, procainamide does not induce lupus erythematosus in mouse models. To explore the differences in this side-effect of procainamide between humans and mouse models, metabolomic analysis using ultra-performance liquid chromatography coupled with electrospray ionization quadrupole time-of-flight mass spectrometry (UPLC-ESI-QTOFMS) was conducted on urine samples from procainamide-treated humans, CYP2D6-humanized mice, and wild-type mice. Thirteen urinary procainamide metabolites, including nine novel metabolites, derived from P450-dependent, FMO-dependent oxidations and acylation reactions, were identified and structurally elucidated. In vivo metabolism of procainamide in CYP2D6-humanized mice as well as in vitro incubations with microsomes and recombinant P450s suggested that human CYP2D6 plays a major role in procainamide metabolism. Significant differences in N-acylation and N-oxidation of the drug between humans and mice largely account for the interspecies differences in procainamide metabolism. Significant levels of the novel N-oxide metabolites produced by FMO1 and FMO3 in humans might be associated with the development of procainamide-induced systemic lupus erythematosus. Observations based on this metabolomic study offer clues to understanding procainamide-induced lupus in humans and the effect of P450s and FMOs on procainamide N-oxidation.
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PMID:Metabolomics reveals the metabolic map of procainamide in humans and mice. 2238 17


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