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)

Activated neutrophils and monocytes were found to metabolize procainamide to a reactive hydroxylamine. In contrast, there was little or no metabolism by lymphocytes or platelets. Therefore, it appears that only leukocytes that contain myeloperoxidase can metabolize procainamide to a significant degree. There was no difference in the degree to which neutrophils from males or females metabolized procainamide; however, monocytes from males formed significantly more hydroxylamine than did monocytes from females. By use of radiolabeled procainamide, covalent binding of procainamide to leukocytes was detected, and the degree of binding correlated with the cells' ability to oxidize procainamide. These findings suggest that myeloperoxidase is the major enzyme involved in the formation of reactive metabolites by leukocytes, a pathway that we propose may be responsible for procainamide-induced lupus and agranulocytosis.
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PMID:Comparative metabolism and covalent binding of procainamide by human leukocytes. 134 86

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

Antineutrophil cytoplasmic antibodies (ANCA) have been described as sensitive and specific markers for active Wegener's granulomatosis (WG). ANCA in WG produce a characteristic cytoplasmic staining pattern of neutrophils (c-ANCA) and are directed against proteinase 3 (Pr3), a serine protease from the azurophilic granules. c-ANCA, more or less equivalent to anti-Pr3, occur in more than 90% of patients with extended WG, in 75% of patients with limited WG without renal involvement, and in some 40% to 50% of patients with vasculitic overlap syndromes suggestive of WG such as microscopic polyarteritis. The presence of c-ANCA is highly specific for those diseases (greater than 98%). Changes of levels of c-ANCA precede disease activity and may be used as guidelines for treatment. Antibodies producing a perinuclear staining of ethanol-fixed neutrophils (p-ANCA) occur in a wide range of diseases. They are directed against different cytoplasmic constituents of neutrophils. Among those, antibodies to myeloperoxidase are found in patients with idiopathic crescentic glomerulonephritis, the Churg-Strauss syndrome, polyarteritis nodosa with visceral involvement, and vasculitic overlap syndromes. Their specificity for this group of necrotizing vasculitides is high (94% to 99%), although they may occur in patients with hydralazine-induced glomerulonephritis, anti-glomerular basement membrane disease, and possibly in some patients with idiopathic systemic lupus erythematosus. Antibodies to leukocyte elastase are incidentally found in patients with vasculitic disorders, whereas lactoferrin antibodies are detected in patients with primary sclerosing cholangitis with or without ulcerative colitis and in rheumatoid arthritis. Their diagnostic significance awaits further studies. p-ANCA of undefined specificity may distinguish ulcerative colitis (sensitivity of 75%) from Crohn's disease (sensitivity of 20%). p-ANCA also occur in autoimmune liver diseases: in 75% of patients with chronic active hepatitis, in 60% to 85% of those with primary sclerosing cholangitis, and in about 30% of patients with primary biliary cirrhosis. Finally, p-ANCA are detected in chronic arthritides and in some 5% of healthy controls. Assessment of their diagnostic value has to await further characterization of the antigens involved, allowing the development of antigen-specific assays.
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PMID:Antineutrophil cytoplasmic antibodies: a still-growing class of autoantibodies in inflammatory disorders. 782 11

The diagnostic potential of assays detecting anti-neutrophil cytoplasm antibodies (ANCA), anti-GBM antibodies and anti-dsDNA antibodies was evaluated by examining sera from time of admission in a consecutive series of 455 patients with biopsy verified primary or secondary glomerulonephritis (GN). ANCA were classified into c- and p-ANCA by indirect immunofluorescence (IIF) and ELISAs using alfa-granule extract, proteinase-3, myeloperoxidase (MPO), elastase and lactoferrin. C-ANCA was virtually confined to 64 patients with systemic small vessel vasculitis, 66-74% being c-ANCA positive. P-ANCA against MPO, seen in 47 patients, segregated through many diagnostic categories of primary and secondary severe GN. ANCA against lactoferrin and elastase were rare. Anti-dsDNA positive patients constituted 57% of the 44 ANA-positive patients with systemic lupus erythematosus. It is concluded that the IIF and ELISAs for anti-proteinase-3, anti-MPO, anti-dsDNA and anti-GBM have an acceptable performance and are useful in the primary diagnostic work-up of patients suspected for secondary GN as the majority of such patients will be classified by these assays.
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PMID:Anti-neutrophil cytoplasm antibodies, anti-GBM antibodies and anti-dsDNA antibodies in glomerulonephritis. 147 49

Evidence strongly suggests that many adverse drug reactions, including idiosyncratic drug reactions, involve reactive metabolites. Furthermore, certain functional groups, which are readily oxidized to reactive metabolites, are associated with a high incidence of adverse reactions. Most drugs can probably form reactive metabolites, but a simple comparison of covalent binding in vitro is unlikely to provide an accurate indication of the relative risk of a drug causing an idiosyncratic reaction because it does not provide an indication of how efficiently the metabolite is detoxified in vivo. In addition, the incidence and nature of adverse reactions associated with a given drug is probably determined in large measure by the location of reactive metabolite formation, as well as the chemical reactivity of the reactive metabolite. Such factors will determine which macromolecules the metabolites will bind to, and it is known that covalent binding to some proteins, such as those in the leukocyte membrane, is much more likely to lead to an immune-mediated reaction or other type of toxicity. Some reactive metabolites, such as acyl glucuronides, circulate freely and could lead to adverse reactions in almost any organ; however, most reactive metabolites have a short biological half-life, and although small amounts may escape the organ where they are formed, these metabolites are unlikely to reach sufficient concentrations to cause toxicity in other organs. Many idiosyncratic drug reactions involve leukocytes, especially agranulocytosis and drug-induced lupus. We and others have demonstrated that drugs can be metabolized by activated neutrophils and monocytes to reactive metabolites. The major reaction appears to be reaction with leukocyte-generated hypochlorous acid. Hypochlorous acid is quite reactive, and therefore it is likely that many other drugs will be found that are metabolized by activated leukocytes. Some neutrophil precursors contain myeloperoxidase and the NADPH oxidase system, and it is likely that these cells can also oxidize drugs. Therefore, although there is no direct evidence, it is reasonable to speculate that reactive metabolites generated by activated leukocytes, or neutrophil precursors in the bone marrow, could be responsible for drug-induced agranulocytosis and aplastic anemia. This could involve direct toxicity or an immune-mediated reaction. These mechanisms are not mutually exclusive, and it may be that both mechanisms contribute to the toxicity, even in the same patient. In the case of drug-induced lupus, a prevalent hypothesis for lupus involves modification of class II MHC antigens.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:The role of leukocyte-generated reactive metabolites in the pathogenesis of idiosyncratic drug reactions. 162 36

A long-term side effect of therapy with a variety of drugs is a syndrome resembling the idiopathic autoimmune disease, systemic lupus erythematosus. Essentially all patients with drug-induced lupus display autoantibodies to nuclear histone components whose specificity appears to be related to the higher order structure of histones existing in chromatin. IgG antibodies to H1 and the (H2A-H2B)-DNA complex were observed in most patients with lupus induced by procainamide, hydralazine, and quinidine, whereas the H3-H4 tetramer, comprising half the mass of the nucleosome core particle, was largely nonantigenic. IgM antibodies to (H2A-H2B)-containing chromatin subunits were common also. IgM reactivity was observed with the DNA-free H3-H4 tetramer and with H1, especially in hydralazine-induced lupus. These results suggest that IgM antihistone antibodies may result from autoimmunization with a nonnative form of chromatin, whereas IgG antibodies may be selected for reactivity with H1 and a native form of the (H2A-H2B)-DNA subunit of the nucleosome. The chemical basis for induction of autoimmunity by drugs is unclear because lupus-inducing drugs do not have a common structural feature or biological activity nor are they capable of specific reactions with histones, the principal target antigen. However, in the presence of activated neutrophils, procainamide is transformed metabolically to the cytotoxic procainamide-hydroxylamine. Mixing experiments and cell-free studies demonstrated that procainamide was cooxidized with H2O2 by myeloperoxidase released when neutrophils undergo the respiratory burst and degranulation reactions. Preliminary results indicate other lupus-inducing drugs are also biotransformed by this mechanism suggesting that a common denominator linking these drugs may be the capacity to be oxidized to reactive metabolites by the action of activated phagocytic cells.
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PMID:Autoantibody specificity in drug-induced lupus and neutrophil-mediated metabolism of lupus-inducing drugs. 163 38

Antibodies directed against myeloperoxidase (anti-MPO) were detected, using a solid-phase ELISA and purified sputum myeloperoxidase as the substrate, in 54 sera from 22 patients. Anti-MPO were present in 17 patients with crescentic glomerulonephritis (CGN), Wegener's granulomatosis (WG) and microscopic polyarteritis (MPA), and thus are associated with different forms of vasculitis. Anti-MPO were also present in five out of 20 patients with systemic lupus erythematosus (SLE). Anti-MPO activity in SLE sera was low, in contrast to the high titers observed in patients with vasculitis. All positive sera had IgG anti-MPO (except two SLE sera) and most of them also contained low-titered IgM anti-MPO. Only three patients had high IgM anti-MPO activities, the significance of which remains to be determined. In patients with CGN, WG or MPA, the anti-MPO titer decreased following therapy and paralleled the disease activity. Thus, anti-MPO constitute a useful diagnostic tool and a sensitive marker of disease activity in this group of patients with vasculitis.
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PMID:Anti-myeloperoxidase antibodies: immunological characteristics and clinical associations. 165 17

In previous studies we had shown that procainamide is metabolized to reactive metabolites by activated leukocytes, and evidence pointed to involvement of myeloperoxidase (MPO). In this study we examine the metabolism of procainamide by MPO/H2O2, in the presence and absence of chloride ion. In the absence of chloride ion, the metabolism was very similar to that seen with activated leukocytes. The major metabolite was formed by oxidation of the arylamine group to a hydroxylamine. In the presence of chloride ion, a much greater degree of metabolism occurred, and the major product (40% of the starting procainamide) was a reactive species that could not be isolated. This metabolite spontaneously rearranged to 3-chloroprocainamide, and from its mass spectrum and chemical reactions, we deduce its structure to be N-chloroprocainamide. The N-chloroprocainamide metabolite reacted very rapidly with reducing agents, such as ascorbate, and also reacted with protein such as albumin, the major product in both cases being procainamide. This metabolite also chlorinated phenylbutazone. When radiolabeled procainamide was oxidized by MPO/H2O2 in the presence of albumin, covalent binding of the radiolabel to albumin occurred, and binding was greater under conditions in which N-chloroprocainamide was formed. It is probable that the failure to observe N-chloroprocainamide, when procainamide is oxidized by activated leukocytes, is due to its rapid reaction with the cells. We propose that modification of neutrophils (or neutrophil precursors in the bone marrow) by these reactive metabolites is responsible for procainamide-induced agranulocytosis. In a similar manner, procainamide-induced lupus could be due to modification of monocytes by monocyte-generated reactive metabolites.
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PMID:N-Chlorination and oxidation of procainamide by myeloperoxidase: toxicological implications. 166 58

Hydralazine is associated with a lupus-like syndrome. There is evidence that many drug hypersensitivity reactions are due to reactive metabolites. Incubation of hydralazine with activated neutrophils or monocytes led to the production of phthalazinone, phthalazine and 3 unidentified metabolites. Formation of the metabolites, with the exception of phthalazine, required activation of the leukocytes. Using radiolabelled hydralazine, covalent binding to activated neutrophils was observed. Oxidation of hydralazine catalyzed by myeloperoxidase (MPO) produced the same metabolites and covalent binding to protein. We conclude that hydralazine is metabolized by activated leukocytes to a reactive metabolite which may be associated with hydralazine induced lupus.
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PMID:Metabolism of hydralazine by activated leukocytes: implications for hydralazine induced lupus. 166 57

Autoantibodies that produce a perinuclear pattern on indirect immunofluorescent examination of ethanol-fixed neutrophils (pANCA) are found in about half of all cases of microscopic polyarteritis. These antibodies are often directed against myeloperoxidase or elastase and we have developed sensitive reproducible ELISAs for their detection and study. Seven sera from 19 patients with microscopic polyarteritis or segmental necrotizing glomerulonephritis contained anti-myeloperoxidase or anti-elastase antibodies or both. In contrast, only one of 18 sera from patients with Wegener's granulomatosis, where the pattern of immunofluorescence is predominantly cytoplasmic, had anti-myeloperoxidase antibodies and no anti-elastase antibodies were detected. Using sera from patients with microscopic polyarteritis, both anti-myeloperoxidase and anti-elastase antibodies were demonstrated to be of high affinity. There was no immunoglobulin class, subclass or light chain restriction noted. Anti-myeloperoxidase and anti-elastase antibodies were also found occasionally in anti-glomerular basement membrane disease, mixed connective tissue disease, systemic lupus erythematosus, post-streptococcal glomerulonephritis and atypical pneumonia. In further studies these antibodies were not associated with other lung infections, although anti-elastase antibodies were noted in one of 14 sera positive for ASOT that were tested. Anti-myeloperoxidase antibodies were found more frequently than anti-elastase antibodies and these antibodies were occasionally present together. In addition some sera with pANCA had neither anti-myeloperoxidase nor anti-elastase antibodies. The target molecules in these cases remain unclear.
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PMID:Detection of anti-myeloperoxidase and anti-elastase antibodies in vasculitides and infections. 185 Oct 56


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