Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0409974 (lupus)
 22,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Reactive metabolites are believed to be responsible for many types of toxicity, including idiosyncratic drug reactions. Bone marrow is a frequent target of idiosyncratic reactions, and, since these reactions have characteristics that suggest involvement of the immune system, the formation of reactive metabolites by leucocytes could also play a role in the aetiology of idiosyncratic drug reactions. The major oxidation system in neutrophils and monocytes is a combination of NADPH oxidase and myeloperoxidase. This system oxidizes primary arylamines, such as sulphonamides, to reactive metabolites and these drugs are also associated with a high incidence of agranulocytosis, generalized idiosyncratic reactions and/ or drug-induced lupus. Clozapine is oxidized by this system to a relatively stable nitrenium ion; clozapine is also associated with a high incidence of agranulocytosis. Arylamines that have an oxygen or nitrogen in the para position, such as amodiaquine, vesnarinone and 5-aminosalicylic acid, are oxidized to quinone-like reactive intermediates. Aminopyrine is oxidized to a very reactive dication. Such reactive metabolites could also inhibit neutrophil function and mediate some of the therapeutic effects of these drugs: for example, the use of dapsone for dermatitis herpetiformis and the use of 5-aminosalicylic acid for inflammatory bowel disease.
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PMID:Myeloperoxidase as a generator of drug free radicals. 866 Mar 93

The antithyroid drug propylthiouracil (PTU) is known to cause adverse immunological side effects, such as a lupus-like syndrome and vasculitic disorders. In vitro experiments have established that myeloperoxidase of activated neutrophils can oxidize PTU to the reactive intermediate propyluracil 2-sulfonate PTU-SO3-, and it has been proposed that PTU-SO3- might be responsible for the PTU-associated side effects. Here, using the direct popliteal lymph node assay (PLNA) in mice we found that PTU-SO3-, indeed, induced a T-cell-dependent primary PLN response, whereas the parent compound PTU failed to do so. As shown by adoptive transfer PLNA, splenic T cells of mice that had received four injections of PTU-SO3- mounted a specific secondary response to the reactive metabolite, but not to PTU. When homogenized peritoneal phagocytes, which had been incubated with PTU in vitro, were used as the antigen, a primary response in the direct PLNA was elicited, suggesting that the phagocytes contained the reactive metabolite. Moreover, T cells sensitized to the reactive metabolite PTU-SO3- were detected in mice that were undergoing long-term treatment with PTU plus an additional treatment with phorbol myristate acetate for stimulation of the oxidative metabolism of their phagocytic cells. Together, these findings support the concept that phagocytes oxidize PTU to its immunogenic metabolite, PTU-SO3-, which then, presumably via covalently binding to self-proteins, induces T cell sensitization.
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PMID:T cells ignore the parent drug propylthiouracil but are sensitized to a reactive metabolite generated in vivo. 876 61

Cats are known to develop a lupus-like syndrome similar to that observed in humans when treated with propylthiouracil. We have previously demonstrated that propylthiouracil and other drugs associated with lupus are oxidized in the presence of myeloperoxidase to reactive intermediates. We postulated that these reactive metabolites could modify myeloperoxidase resulting in anti-myeloperoxidase antibodies and possibly be responsible for the lupus-like syndrome. Five cats were treated with propylthiouracil and 2 developed the lupus-like syndrome as well as anti-myeloperoxidase antibodies. These appeared to correlate better with disease than antinuclear antibodies. The antibodies were true autoantibodies because the myeloperoxidase used to detect the antibodies did not require treatment with propylthiouracil. In a subsequent study in which the cat food contained a higher level of taurine, none of the animals developed the autoimmune syndrome. It is possible that diet also plays an important role in the development of such adverse reactions.
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PMID:Antibodies to myeloperoxidase in propylthiouracil-induced autoimmune disease in the cat. 894 14

Idiosyncratic adverse drug reactions have characteristics that suggest involvement of the immune system. In particular, drug-induced lupus which is an autoimmune syndrome, must be immune-mediated. A major working hypothesis for the first step in the mechanism of drug-induced autoimmunity is that the drug, or more commonly a reactive metabolite of the drug, must irreversibly bind to some structure. In view of the reactive nature of these metabolites, in most cases it is likely that the metabolite must be formed in the organ where toxicity occurs. The liver is the major site of drug metabolism and it is a common target for idiosyncratic drug reactions. In the case of immune reactions directly involving leukocytes, the enzyme system most likely responsible for the formation of reactive metabolites is the NADPH oxidase/myeloperoxidase system found in neutrophils and monocytes. In some cases, the reactive metabolite results in the production of antibodies or T-cells directed against the altered structure. However, in many other cases, the mechanism appears to be more complex than this. In some cases, true auto-antibodies are produced that do not require the presence of the drug, and furthermore, the antibodies produced often are the same as those induced by other stimuli, such as viruses. This suggests either molecular mimicry or a common alteration in the processing and presentation of antigens such that cryptic antigens are presented. Another possibility is that the reactive metabolite directly alters the class II MHC molecule leading to a graft-vs-host reaction.
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PMID:Current trends in drug-induced autoimmunity. 912 93

We aimed to evaluate the presence of peripheral antineutrophil cytoplasmic antibodies (p-ANCA) and cytoplasmic antineutrophil cytoplasmic antibodies (c-ANCA) in children with SLE and to correlate its association of laboratory findings. Twenty-one children with SLE were studied. Serum samples in patients were tested by indirect immunofluorescence (IIF) slide kit (INOVA) for c-ANCA and p-ANCA and by ELISA for myeloperoxidase (MPO-ANCA) and proteinase 3 (PR3-ANCA). All the patients but two were quiescent for lupus at the time of sampling. Sixteen of 21 patients showed positive IIF staining whereas only 5 had MPO-ANCA and 2 of nine PR3-ANCA. The data suggests that SLE may be associated p-ANCA directed against additional target antigens rather than MPO and may be implicated in the pathogenesis of SLE or may be only non-specific antibodies developed in lupus.
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PMID:Antineutrophil cytoplasmic antibodies in childhood systemic lupus erythematosus. 969 70

Drug-induced lupus is a side effect of deliberate ingestion of various medications, but its etiology, underlying mechanisms, and pathogenesis are puzzling. In vivo metabolic transformation of lupus-inducing drugs to reactive products explains how a heterogeneous set of drugs can mediate the same disease syndrome. Evidence has accumulated that drugs are transformed by extracellular oxidation from reactive oxygen species and myeloperoxidase produced when neutrophils are activated, maximizing the in situ accumulation of reactive drug metabolites within lymphoid compartments. The metabolite of procainamide, procainamide hydroxylamine, displays diverse biologic properties, but no apparent autoimmune effect has been observed. However, when procainamide hydroxylamine was introduced into the thymus of young adult normal mice, a delayed but robust autoimmune response developed. Disruption of central T-cell tolerance by intrathymic procainamide hydroxylamine resulted in the production of chromatin-reactive T cells that apparently drove the autoantibody response in the periphery. Drug-induced autoantibodies in this mouse model were remarkably similar to those in patients with procainamide-induced lupus. Therefore, this system has considerable promise to provide insight into the initiating events in drug-induced lupus and may provide a paradigm for how other xenobiotics might induce systemic autoimmunity.
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PMID:Initiation of autoimmunity by a reactive metabolite of a lupus-inducing drug in the thymus. 1050 46

Two IgM, kappa anti-myeloperoxidase (MPO) monoclonal antibodies, 6D6 and 9B5, bound to MPO in a solid-phase enzyme-linked immunosorbent assay were derived from the splenocytes of (NZB x NZW) F1 and MRL/lpr-lpr mice, respectively. 6D6 gave a characteristic perinuclear immunofluorescence staining pattern on ethanol-fixed human neutrophils, bound to the native form of MPO by immunoblotting and had a high constant affinity for MPO as demonstrated by real-time specific interaction. 9B5 produced a cytoplasmic immunofluorescence staining pattern, reacted with the heavy chain of MPO and had a low constant affinity for MPO. The heavy-and light-chain variable region genes of monoclonal antibodies (mAb) 6D6 and 9B5 were sequenced and found to be highly homologous to germline genes and to contain negatively charged amino acids in the complementarity determining regions. IgM MPO-binding activity was observed in most BW and MRL/lpr-lpr mouse sera, which may correspond to polyclonal activation of B cells, whereas IgG anti-MPO antibodies could be rarely detected. Thus, this study indicates that (i) BW and MRL/lpr-lpr mice do not delete IgM anti-MPO secreting B cells, do not maintain these B cells in a state of anergy, but most individuals are not able to spontaneously induce the class-switching of this autoantibody population; (ii) IgM anti-MPO antibodies can recognize different epitopes on MPO and produce different immunofluorescence staining pattern on ethanol-fixed human neutrophils, as demonstrated by the immunochemical properties of the two lupus-mouse derived mAb.
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PMID:IgM anti-myeloperoxidase antibody-secreting lymphocytes are present in the peripheral repertoire of lupus mice but rarely differentiate into IgG-producing cells. 1054 Jan 69

We described four patients who had clinical diagnosis of erythema infectiosum and presented with skin rash, polyarthralgia, polyarthritis, and mild fever. Anti-parvovirus B19 IgM and IgG antibodies were found in all four patients and parvovirus B19 DNA was detected in three of the four patients by polymerase chain reaction (PCR) in sera using standard methods. Anticardiolipin antibody (aCL) was positive in three of the four patients included three with anti-beta2 glycoprotein I (beta2GPI). The immunoglobulin isotype of aCL was found to be IgM. Anti-neutrophil cytoplasmic antibody (ANCA) included three p-ANCA and one c-ANCA was detected in all four patients by indirect immunofluoresence (IIF). Both anti-proteinase 3 (PR3) and anti-myeloperoxidase (MPO) antibodies were found in two patients whom had polyarthritis for more than 6 months. These data indicate parvovirus B19 may be linked to the induction of an autoimmune response.
Lupus 2000
PMID:Parvovirus B19 infection associated with the production of anti-neutrophil cytoplasmic antibody (ANCA) and anticardiolipin antibody (aCL). 1103 24

Antibodies to human myeloperoxidase and cathepsin G have been detected in the serum of some patients with systemic lupus erythematosus. Therefore, the presence of antibodies to human myeloperoxidase and cathepsin G was examined in glomerular immune deposits. Glomerular basement membrane fragments were prepared from renal tissues obtained at autopsy from 19 patients with systemic lupus erythematosus. IgG was extracted from the glomerular basement membrane fragments and tested with sensitive immunoassays for antibodies to myeloperoxidase and cathepsin G. Antibodies to cathepsin G were not detected in the extracts but antibodies to human myeloperoxidase were found in extracts of one specimen. In the extract with 6M guanidine hydrochloride these antibodies were enriched 103-fold, compared to the initial supernatant of glomeruli, which served as a serum surrogate. The recovered antibodies to myeloperoxidase accounted for 12% of the recovered IgG. These findings add autoantibodies to human myeloperoxidase to the list of antibodies that have been shown to be present in glomerular immune deposits of patients with lupus glomerulonephritis.
Lupus 2000
PMID:Antibodies to human myeloperoxidase in glomerular immune deposits of systemic lupus erythematosus. 1103 36

The drug-metabolizing capacity of the liver is well known but cannot account for most idiosyncratic adverse drug reactions. Of the extrahepatic sources of reactive drug metabolites, the neutrophil has received the most attention because of its vast numbers and robust oxidizing machinery. Many drugs associated with autoimmunity are susceptible to oxidative transformation by the enzymatic action of myeloperoxidase, a protein released into the extracellular environment when neutrophils are activated. Production of the resulting drug metabolites within lymphoid organs maximizes their immune-perturbing effects. Mechanisms proposed for the initiation of drug-induced blood dyscrasias, hypersensitivity reactions, or lupus-like symptoms center around three views: (1) presentation of the implicated compound in the major histocompatibility complex of antigen-presenting cells via direct binding or after processing as a hapten bound to self-macromolecules, (2) direct cytotoxicity, or (3) interference in the development of T-cell tolerance in the thymus. How participation of reactive drug metabolites in these processes might lead to symptomatic disease is discussed.
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PMID:Phagocyte-mediated oxidation in idiosyncratic adverse drug reactions. 1113 24


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