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)

The tuberculostatic agent isoniazid has been implicated in inducing various idiosyncratic reactions including drug-induced lupus. The mechanism is unknown but may involve a reactive metabolite of the drug. Isoniazid was oxidized by activated leukocytes to isonicotinic acid. Myeloperoxidase is likely the enzyme in the leukocyte involved, since the oxidation was inhibited by azide, which inhibits myeloperoxidase, and by catalase, which catalyzes the breakdown of hydrogen peroxide. The same metabolic profile was observed when isoniazid was incubated with purified myeloperoxidase and hydrogen peroxide. The rate of the reaction was increased in the presence of chloride. Hypochlorous acid was also able to oxidize isoniazid to isonicotinic acid. Isoniazid, or an oxidative product, inhibited the reaction when high initial substrate concentrations were used. Isoniazid is oxidized by activated leukocytes, possibly to a reactive intermediate, which may have implications for isoniazid-induced lupus.
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PMID:Metabolism of isoniazid by activated leukocytes. Possible role in drug-induced lupus. 135 11

Hydralazine caused site-specific DNA damage in the presence of Cu(II), Co(II), Fe(III), or peroxidase/H2O2. The order of inducing effect of metal ions on hydralazine-dependent DNA damage [Cu(II) greater than Co(II) greater than Fe(III)] was related to that of accelerating effect on the O2 consumption rate of hydralazine autoxidation. Catalase completely inhibited DNA damage by hydralazine plus Cu(II), but hydroxyl radical (.OH) scavengers and superoxide dismutase did not. On the other hand, DNA damage by hydralazine plus Fe(III) was inhibited by catalase and .OH scavengers. Hydralazine plus Cu(II) induced piperidine-labile sites predominantly at guanine and some adenine residues, whereas hydralazine plus Fe(III) caused cleavages at every nucleotide. Activation of hydralazine by peroxidase/H2O2 caused guanine-specific modification in DNA. ESR-spin trapping experiment showed that .OH and superoxide are generated during the Fe(III)- or Cu(II)-catalysed autoxidation of hydralazine, respectively, and that nitrogen-centered radical is generated during the Cu(II)- or peroxidase-catalysed oxidation. The generation of nitrogen-centered radical was also supported by HPLC-mass spectrometry. The results suggest that the guanine-specific modification by the enzymatic activation of hydralazine is due to the nitrogen-centered hydralazyl radical or derived active species, whereas .OH participates in DNA damage by hydralazine plus Fe(III). The mechanism of hydralazine plus Cu(II)-induced DNA damage is complex. The possible role of the DNA damage induced by hydralazine in the presence of Cu(II) or peroxidase/H2O2 is discussed in relation to hydralazine-induced lupus, mutation, and cancer.
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PMID:Free radical production and site-specific DNA damage induced by hydralazine in the presence of metal ions or peroxidase/hydrogen peroxide. 184 78

Factors that potentially affect the generation of excess low molecular weight DNA (LMW-DNA) in cultured phytohemagglutinin (PHA)-stimulated lymphocytes of patients with systemic lupus erythematosus (SLE) were studied because this species of DNA is consistently found and this DNA may play a role in the pathogenesis of the disease. Superoxide dismutase (SOD; 0.05 mg/mL), a scavenger of free radical oxygen, decrease LMW-DNA formation in lymphocytes by 22%. Co-cultivation with cysteamine, a second scavenger of free radical oxygen and a sulfhydryl radioprotective agent, resulted in a 32% decrease in the generation of excess LMW-DNA at a concentration of 0.5 x 10(-3) mol/L and largely prevented its formation at 1.0 x 10(-3) mol/L. Other free radical scavengers (catalase, mannitol, vitamins C and E), cyclooxygenase inhibitors (ibuprofen and aspirin), a xanthine oxidase inhibitor (allopurinol), and an iron chelator (desferoxamine) did not affect excess LMW-DNA formation. Glutathione (1 x 10(-3) mol/L) had no effect and cysteine was toxic. Because scavengers of free radicals might be useful in the therapy of lupus, a trial of cysteamine (30 to 60 mg/kg/d) was administered to six acutely ill patients with SLE. A therapeutic benefit was not demonstrated, and some patients had exacerbation of disease. Lymphocyte cell growth from control and lupus subjects was stimulated when cysteamine, 1 x 10(-5) to 1 x 10(-4) mol/L was added to the media, but inhibited at concentrations of 2 x 10(-4) mol/L or greater. These studies suggest that the autooxidation and toxicity of high-dose cysteamine preclude its therapeutic use as a free radical scavenger.
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PMID:Scavengers of free radical oxygen affect the generation of low molecular weight DNA in stimulated lymphocytes from patients with systemic lupus erythematosus. 224 68

The degree of complement activation produced by hydrogen peroxide was estimated by the inhibition of serum homolytic activity (% IHA). Sera from patients with systemic lupus erythematosus and psoriasis vulgaris were resistant to hydrogen-peroxide-mediated complement activation. %IHA negatively correlated with ceruloplasmin level or catalase activity in systemic lupus erythematosus sera, but did not correlate with transferrin level. The addition of free metal ions, FeCl2 or CuCl2, promoted hydrogen-peroxide-mediated complement activation. These results suggest that hydroxyl radical is involved in complement activation and that the factors responsible for the insensitivity of pathological sera to H2O2 are catalase and ceruloplasmin in the sera. Human skin fibroblasts generate superoxide and tumor necrosis factor enhanced it, but interleukin-1 beta inhibited it. Normal serum cultured with fibroblasts for 24 h showed complement activation via catalase-inhibitable process, suggesting that hydrogen peroxide has an important role in fibroblast-mediated complement activation. It is speculated that fibroblasts and complement activation by oxygen radicals have an important role in inflammation and subsequent tissue damage at the site of skin lesion.
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PMID:Possible role of H2O2-mediated complement activation and cytokines-mediated fibroblasts superoxide generation on skin inflammation. 255 Feb 83

To examine the possible correlation between tissue injury and neutrophil-produced active oxygen (AO) species in patients with systemic lupus erythematosus (SLE), we studied the capacity of the serum from six patients with untreated, active SLE to generate AO and release lysosomal enzymes by normal neutrophils. Cultured endothelial cells from human umbilical cord vein were incubated with serum-stimulated neutrophils to assess AO-induced tissue injury. Serum from patients with bacterial infections and healthy individuals served as controls. AO production was highest in the neutrophils stimulated with SLE patient-derived serum, while lysosomal enzyme release was only slightly increased. SLE neutrophils with or without stimulation and SLE serum-stimulated normal neutrophils produced significantly high levels of cytotoxicity upon coincubation with 51Cr-labeled human endothelial cells. These excessive cytotoxicities were reversed by the presence of superoxide dismutase and catalase, indicating the specificity of the AO effect on endothelial cell damage. These findings suggest that tissue damage in SLE may be partially due to excessive production of AO and that both neutrophils themselves and a serum factor which activates neutrophils are involved in the mechanism for vascular injury.
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PMID:Role of stimulated neutrophils from patients with systemic lupus erythematosus in tissue injury, with special reference to serum factors and increased active oxygen species generated by neutrophils. 298 76

An absolute indication for thymectomy exists in all cases with tumors of the thymus gland, however, preoperative differentiation between benign and malignant lesions is not always possible even with modern imaging methods. In extensive tumors of questionable operability preoperative transthoracic needle biopsy (guided by CAT-scan) is recommended. After establishing the histological diagnosis, preoperative radio- and/or chemotherapy can be considered. Certain immunological diseases are a relative indication for thymectomy. Its value is proven in myasthenia gravis, questionable however in ulcerative colitis and erythroblastopenia. Systemic lupus erythematosus is a contraindication.
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PMID:[Indications for thymectomy]. 310 Aug 86

A patient with two attacks of glottis angioedema in a 15-day period without any apparent stimulus was studied. The complement profile of the patient revealed depletion of C4, C2, C1 inhibitor (C1INH) and C1q, with normal values of C3. Patient's offspring had a normal complement profile. Cytofluorographic analysis of the peripheral blood cells showed a marked increase of B cells. In the clotting study, a circulating lupus-like anticoagulant activity (LLA) was detected with a noticeable decrease of prothrombin time. Hepatosplenomegaly was confirmed by abdominal echography and CAT. From the liver biopsy it was concluded to be a lymphoproliferative process compatible with germinal center lymphoma. It is suggested that the neoplasm is probably the origin of the LLA and the cause of C1 activation, producing the biochemical defect of C1INH and the clinical symptoms of angioedema.
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PMID:Acquired C1-inhibitor deficiency associated with a lupus-like anticoagulant activity. 314 11

Zymosan-stimulated neutrophils from 6 patients with untreated, active systemic lupus erythematosus (SLE), from patients with bacterial infections, and from healthy controls, were studied for production of oxygen intermediates (O-2, H2O2, OH . and chemiluminescence) and lysosomal enzymes. Oxygen intermediate production was highest in neutrophils from active SLE patients, while lysosomal enzyme release was highest in neutrophils from patients with bacterial infections. SLE neutrophils, upon culture with autologous or normal lymphocytes, markedly reduced the number of surviving OKT4+ cells and the proliferative response of the surviving cells to mitogens; a reduction was also observed amongst the surviving lymphocytes in the proportion of total T cells and OKT8+ cells, and in the generation of Con A induced suppressor activity. When superoxide dismutase and catalase were included in the neutrophil-lymphocyte co-cultures, the number of T- and OKT8+ cells, and the suppressor activity were restored but not completely (60-75%), the lymphocyte mitogenic response and number of OKT4+ cells were less well restored (40-50%). When lymphocytes were co-cultured with neutrophils from healthy or infected subjects, there was a mild decrease in mitogenic responses and OKT4+ cells, while the suppressor T-cell activity was markedly enhanced. These results were not affected by scavengers. These results suggest that in SLE, reduced T-lymphocyte subpopulations and altered immunoreactivity may be partially due to excessive production of oxygen intermediates and probably other factors by stimulated neutrophils; these results further suggest that in all the subjects, diseased or healthy, neutrophils generate unidentified factors other than oxygen intermediates that reduce the generation of OKT4+ cells and lymphocyte mitogenic responses, and that potentiate suppressor T-cell activity.
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PMID:Role of stimulated neutrophils from patients with systemic lupus erythematosus in disturbed immunoreactivity, with special reference to increased oxygen intermediates generated by the neutrophils. 608 29

This article gives a synopsis of the inflammatory reactions as well as its mediators under special consideration of the efferent part of the reaction. There is no doubt that histamine, complement, and the kinin system play an essential role; arachidonic acid (eicosatetraenic acid) and its metabolites, however, have gained comparable significance: prostaglandines, prostacyclines, and thromboxanes as metabolites of the cyclo-oxygenase, the leucotrienes SRS-A (slow reacting substances of anaphylaxis) and ECF (eosinophilic chemotactic factor) mediated via lipoxygenase. Moreover, oxygen and its metabolites hydrogen peroxide (H2O2), peroxide radicals (O-2), and hydroxyl radicals (.OH) as well as activated oxygen (singulett oxygen (1O2) play an important part with all aerobic living organisms. Inborn enzyme deficiency of the oxygen metabolism such as NADPH oxidase or cytochrome b-245 deficiency lead to chronic septic granulomatosis. The disease is characterized by reduced resistence against infections, decreased phagocytosis, insufficient killing of bacteria by leucocytes, and diminished oxygen burst. Thus the underlying enzyme deficiency leads to reduced formation of peroxide radicals frequently causing infections with septic complications. On the other hand, increased formation or reduced degradation of peroxide radicals may result in pathological reactions like chromosomal alterations, lipidperoxidation or oxidation of sulph-hydryl groups. The fact that increased peroxide radical formation may cause inflammation or chromosomal aberration is of importance with regard to the pathogenesis of several chronic inflammatory diseases of unknown etiology, such as systemic scleroderma or lupus erythematodes. The enzyme superoxide dismutase (SOD) converts peroxide radicals (O-2) into hydrogen peroxide (H2O2) which can be inactivated by catalase or peroxidase. Consequently, treatment with SOD may have an effective influence on chronic inflammatory dermatoses of unknown pathogenesis.
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PMID:[Biochemical aspects of the inflammatory reaction - with special reference to oxygen]. 666 95

Enrichment of diet with omega-3 lipid rich-menhaden fish oil (FO) when fed ad libitum to autoimmune lupus-prone NZB/NZW F1 (B/W) female mice delayed the onset and slowed progression of renal disease while significantly extending life-span compared to omega-6 lipid rich-corn oil (CO)-fed mice. Northern blot analysis of kidneys from FO-fed mice revealed no detectable levels of IL-1 beta, IL-6 and TNF alpha mRNA contrasted to levels that were easily detected in CO-fed mice. In contrast to the cytokines, FO-fed mice showed higher renal levels of the antioxidant enzymes-catalase, glutathione peroxidase (GSH-Px), superoxide dismutase (SOD)-mRNAs compared to CO-fed mice. The results suggest that dietary supplementation with FO, as compared to CO, inhibits the production of pro-inflammatory cytokines and ameliorates immune-complex-mediated kidney injury possibly by enhancing the ability of cells to dispose of harmful reactive oxygen intermediates.
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PMID:Decreased pro-inflammatory cytokines and increased antioxidant enzyme gene expression by omega-3 lipids in murine lupus nephritis. 817 24


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