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)

Impaired clearance of circulating and/or deposited immune complexes (IC) by the mononuclear phagocytic system is one of the major factors in the pathogenesis of IC diseases. MRL/Mp-lpr/lpr (MRL/lpr) lupus mice spontaneously develop a lethal glomerulonephritis associated with IC deposition. The ability of macrophages to degrade phagocytozed IC and regulation of this degradation in MRL/lpr mice were examined. In 4-month-old MRL/lpr mice, macrophages accumulated in the affected glomeruli and these macrophages contained many phagosomes containing electron-dense bodies. When culture supernatant of human T cell line HUT102 was administered intraperitoneally into disease-bearing MRL/lpr mice, degradation of these electron-dense bodies in the macrophages in glomeruli was noted. We developed a quantitative in vitro assay for IC degradation activity of MRL/lpr resident peritoneal macrophages (RPM) using peroxidase-labelled IC derived from MRL/lpr mouse sera. The ability of the RPM to degrade IC was remarkably enhanced by the pretreatment with HUT102 cell products and the related human recombinant cytokines, lymphotoxin and IL-1 alpha. Moreover, pretreatment of RPM from non-diseased MRL/Mp-+/+ mice with the culture supernatant of spleen cells from diseased MRL/lpr mice reduced their IC degradation activity. These results suggested that the ability of macrophages to degrade IC in MRL/Mp strains of mice is under the regulation of cytokines, and the impaired ability in the disease-bearing mice may be the result of abnormalities in the cytokine system in these mice.
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PMID:Immune complex-degradation ability of macrophages in MRL/Mp-lpr/lpr lupus mice and its regulation by cytokines. 828 94

Carbamazepine is an anticonvulsant which is associated with a significant incidence of hypersensitivity reactions including agranulocytosis. We have postulated that many drug hypersensitivity reactions, especially agranulocytosis and lupus, are due to reactive metabolites generated by the myeloperoxidase (MPO) (EC 1.11.1.7) system of neutrophils and monocytes. This led to a study of the metabolism and covalent binding of carbamazepine with MPO/H2O2/Cl- and neutrophils. Metabolism and covalent binding were observed in both systems and the same pathway appeared to be involved; however, the metabolism observed with the MPO system was approximately 500-fold greater than that observed with neutrophils. The metabolites identified were an intermediate aldehyde, 9-acridine carboxaldehyde, acridine, acridone, choloroacridone, and dichloroacridone. We postulate that the first intermediate in the metabolism of carbamazepine is a carbonium ion formed by reaction of hypochlorous acid (HOCl) with the 10,11 double bond. Although we have no direct proof for the proposed carbonium ion, it provides the most likely mechanism for the observed ring contraction. Iminostilbene, a known metabolite of carbamazepine, was also metabolized by a similar pathway leading to ring contraction; however, the rate was much faster and the first step may involve N-chlorination and a nitrenium ion intermediate. These data confirm that carbamazepine is metabolized to reactive intermediates by activated leukocytes. Such metabolites could be responsible for some of the adverse reactions associated with carbamazepine, especially reactions such as agranulocytosis and lupus which involve leukocytes.
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PMID:Carbamazepine metabolism to a reactive intermediate by the myeloperoxidase system of activated neutrophils. 838 60

The anti-hypertensive agent hydralazine can cause a lupus-like syndrome characterized by serosal inflammation, arthralgias and rashes. The kidneys however are usually spared. The condition is characterized by circulating immune complexes and antinuclear antibodies, whilst antibodies against double-stranded DNA are rare. Hydralazine can also cause a systemic vasculitis with a pauci-immune rapidly progressive glomerulonephritis, which is associated with autoantibodies directed against components of the neutrophil cytoplasm. In this study, ten patients with hydralazine-induced vasculitis had antibodies with specificities for both myeloperoxidase and lactoferrin. We suggest that this particular pattern of autoantibodies, together with antibodies with reactivity against nuclear components including double-stranded DNA, are characteristic findings in hydralazine-induced vasculitis. In addition, renal involvement appears to be more common in this group of patients with vasculitis than in those with the lupus-like syndrome.
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PMID:Antigen specificity in hydralazine associated ANCA positive systemic vasculitis. 854 62

We determined the occurrence of antineutrophil cytoplasmic antibodies (ANCAs) and their specificities in 77 rheumatoid arthritis (RA) patients and compared them with 25 patients with psoriatic arthritis (Pso), 19 with drug-induced lupus erythematosus (DI-LE) and 11 with systemic lupus erythematosus (SLE). Thirty-two percent of RA patients had positive indirect immunofluorescence (IIF) stains (P or atypical ANCA). Twenty-nine per cent of patients with rheumatoid vasculitis (RAV), 48% with long-standing RA (LSRA) and 20% with early RA (Ely RA) had positive ANCAs compared with 4% of Pso patients, 47% of DI-LE patients and 45% of SLE patients. Western blotting (with polymorphonuclear cell extracts or alpha-granules) and alpha-granule enzyme-linked immunosorbent assay (ELISA) yielded variable results and proved unhelpful for characterizing the specificities of ANCAs. ELISAs based on commercial purified lactoferrin (LF), myeloperoxidase (MPO), human elastase (HLE) and cathepsin G (CG) showed that anti-HLE antibody was the most prevalent (14%) antibody in RA, followed by anti-MPO antibody and anti-LF antibody (10% each). Statistical analysis of antibody prevalence by clinical presentation showed that LSRA patients were more likely to have anti-HLE antibody and that DI-LE patients were more likely to have anti-CG antibody compared with the other patient groups. In lupus patients serial ELISA titration of ANCAs (LF and MPO) was found to be reliable for predicting the outcome. The overall incidence of ANCAs in RA patients was 33% by IIF.
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PMID:Antineutrophil cytoplasmic antibodies in rheumatoid arthritis patients. 862 21

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

Hydrazines are believed to be oxidized by peroxidases to reactive intermediates responsible for a variety of adverse side effects including cancer and drug-induced lupus. However, hydrazines are regarded as a poor peroxidase substrates because inactivation of the peroxidase occurs during oxidation of these compounds. We have investigated the hypothesis that efficient peroxidase substrates, termed mediators, may stimulate peroxidase-catalyzed oxidation of hydrazines to intermediates capable of causing DNA damage. Oxidation of hydralazine by horseradish peroxidase was stimulated, enzyme inactivation was significantly decreased, and DNA strand breakage was enhanced by the addition of chlorpromazine. Similar results were obtained using other peroxidases, mediators, and hydrazine derivatives. DNA damage required the addition of a minimum of 3 equiv of hydrogen peroxide, suggesting the involvement of a three-electron oxidation product of hydralazine in DNA damage. Efficient substrates may therefore play a critical role in peroxidase-dependent oxidative metabolism and subsequent damage to biological macromolecules by certain chemicals.
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PMID:Peroxidase substrates stimulate the oxidation of hydralazine to metabolites which cause single-strand breaks in DNA. 908 13

Reactive oxygen species (ROS) are cytotoxic, causing inflammatory disease, including tissue necrosis, organ failure, atherosclerosis, infertility, birth defects, premature aging, mutations and malignancy. ROS are produced in the metabolism of drugs and industrial chemicals by (i) one-electron peroxidase oxidations to form cation radicals, (ii) cytochrome P450 metabolism to free radical products, (iii) stabilisation of the ROS-generator, CYP2E1, and (iv) futile cycling of other cytochromes P450. ROS production initiates inflammation which unless quenched may result in chronic inflammatory disease states, e.g. hepatitis, nephritis, myositis, scleroderma, lupus erythematosus, multiple system organ failure. Quenching of ROS is affected by the redox buffer, glutathione (GSH), and the antioxidants, ascorbic acid, tocopherols, retinoids, in conjunction with the redox enzymes, GSH reductase, GSH peroxidase, catalase and superoxide dismutase. Many industrial workers with symptoms of systemic inflammation, resulting from exposure to toxic chemicals, are diagnosed as having rheumatoid arthritis, virus infections, or other microbial lesions, largely because many physicians are unaware that exposure to certain chemicals can initiate inflammatory disease states.
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PMID:Chemical toxicity and reactive oxygen species. 911 92

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


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