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)

Inhibition of prostaglandin synthesis at the prostaglandin synthetase and phospholipase steps could account for acute changes in renal function which are sometimes induced in patients with systemic lupus erythematosus (S.L.E.) by nonsteroidal anti-inflammatory drugs and high-dose corticosteriids, respectively. Renal function in S.L.E. patients seems to be more susceptible to inhibition of prostaglandin synthesis than in normal subjects. This susceptibility, in conjunction with increased urinary excretion of prostaglandin compounds, indicates that renal function in S.L.E. patients may depend on enhanced renal prostaglandin production for the maintenance of renal haemodynamics.
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PMID:Renal prostaglandins in systemic lupus erythematosus. 7 20

This review presents a unifying hypothesis that provides a connection between several types of hypersensitivity reactions associated with several types of drugs and explains some of the therapeutic effects (antiinflammatory activity and antithyroid effects) of these same drugs. This hypothesis centers on the oxidation of these drugs to chemically reactive metabolites by peroxidases. The drugs of interest have functional groups that are easily oxidized. The major peroxidase involved in this hypothesis is MPO because of its critical location in leukocytes which play a key role in the function of the immune system. However, thyroid peroxidase can probably also oxidize many of the same drugs to reactive metabolites, and this may be responsible for the thyroid autoimmunity observed in connection with some hypersensitivity reactions. Peroxidases have also been described in the skin and in platelets, and their presence may be responsible for the high incidence of skin reactions in the hypersensitivity response and the occurrence of immune-mediated thrombocytopenia, respectively. Involvement of other peroxidases, such as prostaglandin peroxidase, may also be important for antiinflammatory effects of drugs. In addition, leukocytes contain prostaglandin synthetase, and the activation of leukocytes leads to the release of arachidonic acid and the production of prostaglandins. This process may also lead to the metabolism of drugs to reactive metabolites. In studies of the metabolism of procainamide and dapsone, aspirin and indomethacin did not inhibit the formation of the hydroxylamine by neutrophils and mononuclear leukocytes. This is evidence against the involvement of prostaglandin synthetase in these oxidation; however, preliminary studies with other drugs suggest that prostaglandin synthetase may contribute to the metabolism of some drugs by leukocytes. Furthermore, the metabolism of phenylbutazone, phenytoin, and tenoxicam, as well as our preliminary work with other drugs such as carbamazepine, suggests that the range of drugs that are metabolized to reactive metabolites by peroxidases may be broader than initially suspected. There are several other drugs that do not fit into the functional group classes covered in this review but have similar properties. A good example is alpha-methyldopa, which is associated with drug-induced lupus, immune-mediated hemolytic anemia, and other hypersensitivity reactions. Such drugs may also be metabolized to reactive metabolites by peroxidases. Another aspect of the hypothesis is that an infection, or other inflammatory condition, may be an important risk factor for a hypersensitivity reaction because such a stimulus leads to activation of leukocytes which can lead to formation of reactive metabolites from certain drugs.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Drug metabolism by leukocytes and its role in drug-induced lupus and other idiosyncratic drug reactions. 217 25

The effect of polymorphonuclear leukocytes (PMNs) on lymphocyte subpopulations and their reactivity was investigated by adding supernatants obtained by culturing PMNs with allogeneic or autologous lymphocytes which had been pre-treated with prostaglandin (PG) synthetase inhibitors. PMNs were obtained from 12 healthy individuals, 7 patients with systemic lupus erythematosus (SLE) and 6 patients with bacterial infections. Freshly prepared normal lymphocytes pretreated with PG synthetase inhibitors were incubated with the above supernatants, and the lymphocyte and T-lymphocyte subpopulations were then quantitated, the responses of lymphocytes to mitogens measured and the generation of helper and suppressor T-cell activities for PWM-stimulated cultures assessed. We also ascertained which T-cell population, i.e. OKT4+ or OKT8+ cells, which had been altered by incubation with supernatants, was responsible for the suppressor T-cell activity. A reduced per cent of OKT4+ cells; depressed responses to Con A, PHA, PWM and allogeneic lymphocytes, impaired helper T-cell activity; and increased suppressor T-cell activity were noted after incubation of lymphocytes with supernatants. The percentage of T lymphocytes and of OKT8+ cells was, however, not affected. Further, enhanced suppressor T-cell activity was obtained when supernatant-incubated OKT4+ cells were cultured with OKT8+ cells, regardless of whether the latter had previously been exposed to supernatants. Addition of PG inhibitors to PMN co-cultures nearly restored the original percentage and reactivity of the T-lymphocyte populations, indicating a role for PG released from PMNs in the effects observed. The amount of PG demonstrated in co-culture supernatants was 30 times more than obtained by sonification of fresh PMNs and 10 times more than found in the culture medium containing PMNs alone. These results suggest that, besides monocytes, other phagocytes, including PMNs, can modulate lymphocyte-mediated immune reactivity by the release of PG. Deceased number of OKT4+ cells, impaired helper T-cell activity and enhanced suppressor cell activity may, at least in part, result from the effect of PG released from PMNs as well as monocytes.
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PMID:Modulation of the immunoreactivity of a T-lymphocyte subpopulation by neutrophil-released prostaglandin. 293 29

We examined the effects of two prostaglandin synthetase inhibitors, aspirin and oxaprozin, on the development of lupus-like disease in MRL/1 mice. Daily oral administration of 100 mg/kg of these compounds over a period of 3 months significantly reduced thymic lymphoid hyperplasia. In addition, aspirin but not oxaprozin significantly lowered total lymphocyte counts in the peripheral blood. Other drug-related changes, including reduced hyperplasia in the spleen and lymph nodes and an improvement in kidney vasculitis by aspirin, did not reach statistical significance. Neither aspirin nor oxaprozin influenced the circulating levels of anti-ds DNA antibodies or the severity of kidney glomerulonephritis. While the overall effects of these cyclooxygenase inhibitors were not dramatic, the results do indicate that further studies are warranted to determine the precise therapeutic role, if any, for PG-synthetase inhibitors in lupus-like disease.
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PMID:Effects of oral aspirin and oxaprozin on the development of lupus-like disease in MRL/1 mice. 643 13

T cell colony growth in semisolid medium, a sensitive indicator of disease-associated lymphoycte defects, was found to be depressed in patients with PSS and RA. In both disorders, more pronounced abnormalities were observed after incubation with suboptimal concentrations of the polyclonal mitogen PHA. Depletion of monocytes by adherence to plastic surfaces of addition of the prostaglandin synthetase inhibitor indomethacin did not correct the growth abnormality observed in PSS. Reduced colony-forming activity could not be attributed to serum inhibitory factors. The cellular abnormalities detected in patients with these connective tissue diseases were less pronounced than those found in SLE patients.
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PMID:Reduced T lymphoid colony growth in patients with progressive systemic sclerosis and rheumatoid arthritis. 698 Feb 49

2 patients with systemic lupus erythematosus and mild renal functional impairment were treated with ibuprofen, one of the phenylproprionic nonsteroidal anti-inflammatory drugs. Within days after the onset of therapy, both developed renal insufficiency manifested by elevated serum creatinine levels, increased proteinuria, and active urinary sediments; 1 patient was oliguric. Renal biopsies disclosed mesangial proliferative lupus glomerulonephritis and acute tubular necrosis, the latter more pronounced in the oliguric patient. Renal failure resolved following discontinuation of ibuprofen and supportive therapy. It is postulated that altered blood flow, mediated through the well-known prostaglandin synthetase inhibitory effects of ibuprofen, resulted in tubular necrosis. This undesirable complication of ibuprofen therapy may be enhanced in patients with underlying renal disease, and may be a factor governing the limitation of its usage.
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PMID:Ibuprofen-induced acute renal failure with acute tubular necrosis. 718 Sep 1

A typical feature of lupus nephritis is glomerular and interstitial leukocyte infiltration. In search of a serological marker of renal disease activity, we examined prostaglandin endoperoxide synthetase (PGHS) activity in peripheral-blood monocytes isolated from 5 healthy subjects and 11 untreated patients with biopsy-proven lupus nephritis, using radioimmunoassay of prostaglandin E2 (PGE2) and thromboxane B2 (TxB2) released during 24-hour cultures with selective stimuli/inhibitors. Unstimulated basal PGE2 and TxB2 synthesis, reflecting in vivo PGHS activity, was greater in the five patients with active renal involvement (World Health Organization [WHO] classes IVb-c) and the six lupus patients without active disease than in the five healthy subjects (TxB2, 2,643+/-198 [standard error], 2,015+/-190, 1,548+/-295 pg/10(6) cells, respectively). Escherichia coli lipopolysaccharide (LPS; 10 microg/mL) potently induced TxB2 or PGE2 synthesis in healthy controls (+255%+/-76% and +611%+/-190%, +688%+/-234% and +3,189%+/-154%; 4 to 24 hours, respectively), an effect abolished by 5 micromol/L of dexamethasone (DEX) or by 5 micromol/L of the protein synthesis inhibitor cycloheximide (CHX). Responses to LPS were reduced in lupus patients without disease activity and reduced even further in those with active nephritis. This may be related to substrate depletion or feedback functional inhibition of the inducible isoform of PGHS. Our assay may prove useful in the early detection of kidney disease activity in lupus erythematosus.
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PMID:Eicosanoid synthesis in peripheral blood monocytes: a marker of disease activity in lupus nephritis. 982 Apr 47