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)

The use of the antihypertensive hydralazine is associated with an autoimmune syndrome resembling systemic lupus erythematosus. Adverse drug reactions, such as drug-induced lupus, often involve reactive intermediates. Oxidation of hydralazine by liver microsomes or activated leukocytes leads to reactive intermediates that covalently bind to protein and may be involved in hydralazine-induced lupus. Oxidation of hydralazine to a reactive intermediate by cells involved in immune response, such as leukocytes, would be more likely to lead to an autoimmune reaction, such as drug-induced lupus, than would oxidation by cells in the liver. Leukocytes possess a defense system that generates HOCl in response to invading microorganisms. Hydralazine was oxidized to a reactive intermediate by HOCl generated by activated leukocytes. The reactive intermediate was trapped with N-acetylcysteine and the adduct was identified as 1-phthalazylmercapturic acid. The reactive intermediate is likely the diazonium salt of hydralazine. Two stable products were formed in the reaction, phthalazine and phthalazinone. Although phthalazine is oxidized to phthalazinone by HOCl, the rate of the reaction is much too slow to explain the rapid production of phthalazinone. It is more likely that most of the phthalazinone is formed by reaction of the putative diazonium salt with water. We propose that this reactive metabolite is responsible for hydralazine-induced lupus.
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PMID:Reactive intermediates in the oxidation of hydralazine by HOCl: the major oxidant generated by neutrophils. 826 46

Inflammation produces reactive oxygen intermediates (ROI) that cause vascular damage and activate T lymphocytes. Conversely, antioxidants not only protect tissue from oxidative damage but also suppress immune reactivity. The objective of this study was to examine immunomodulatory effects of the non-enzymatic antioxidants, N-acetylcysteine (NAC) and cysteamine (CYST), on autoimmune disease, glomerulonephritis, and mortality in the female B/W mouse model of human systemic lupus erythematosus (SLE). The development of murine lupus was assessed during the lifespan of female B/W mice given NAC or CYST. Morbidity and mortality were assessed daily. At 6 week intervals mice were examined for weight change, albuminuria, serum BUN, antibodies to DNA, and IgG immunoglobulin levels. Serum prolactin, estrogen and progesterone were measured at 18 weeks of age. In a parallel study, NAC- and CYST-treated and control B/W mice were examined at 24 weeks of age for interval renal histopathology, lymphocyte adhesion molecule expression, and antibody titers and in vitro cytokine production in response to immunization with DNP-KLH. CYST significantly suppressed development of albuminuria and azotemia at 36 and 42 weeks of age compared to control and NAC-treated mice. NAC significantly suppressed anti-DNA antibody levels at 24 weeks. In contrast CYST significantly increased anti-DNA antibody levels at 18 weeks of age (P < 0.001 CYST vs control and NAC-treated mice). Kidneys of CYST-treated mice also had accelerated inflammatory histologic changes despite their lower incidence of albuminuria and azotemia. Mean (+/- s.e.m.) survival of control mice was 33 +/- 2 weeks compared to 38 +/- 2 weeks in NAC-treated mice (P < 0.05 vs control), and 48 +/- 2 weeks in the CYST-treated group (P < 0.01 vs control mice). The antioxidants, NAC and CYST, significantly improved mortality in the female B/W mouse model of SLE. NAC suppressed autoantibody formation and modestly prolonged survival. CYST, despite its augmentation of anti-DNA levels and renal inflammatory changes, inhibited the development of renal insufficiency and markedly improved survival. These findings suggest that ROIs play a role in the pathogenesis of lupus nephritis and that antioxidants reduce the damage causing renal insufficiency. Antioxidants may be a beneficial adjunctive therapy in the treatment of human SLE.
Lupus 2001
PMID:Antioxidants suppress mortality in the female NZB x NZW F1 mouse model of systemic lupus erythematosus (SLE). 1134 Nov 2

Of the tetracyclines, minocycline is unique in causing a significant incidence of a lupus-like syndrome and autoimmune hepatitis. It is also unique among the tetracyclines in having a para-N,N-dimethylaminophenol ring. Many drugs that cause autoimmune reactions are oxidized to reactive metabolites by the myeloperoxidase (MPO) system of macrophages. In this study, we showed that minocycline is oxidized to reactive intermediates by MPO/H(2)O(2)/Cl(-), HOCl, horseradish peroxidase/H(2)O(2), or hepatic microsomes. When trapped with N-acetylcysteine (NAC), two adducts with protonated molecular ions at m/z 619 were isolated and analyzed by NMR. One represents attack of the aromatic D ring by NAC meta to the N,N-dimethylamino group, which implies that the reactive intermediate was a quinone iminium ion. The NMR of the other adduct, which was not observed when minocycline was oxidized by hepatic microsomes, indicates that the NAC is attached at the junction of the B and C rings. In the oxidation by HOCl, we found an intermediate with a protonated molecular ion of m/z 510 that represents the addition of HOCl to minocycline. The HOCl presumably adds across the double bond of the B ring, and reaction of this intermediate with NAC led to the second NAC adduct. We were surprised to find that the same NAC adduct was not observed after oxidation of tetracycline with HOCl, even though this part of the tetracycline structure is the same as for minocycline. We propose that one or more of these reactive metabolites are responsible for the idiosyncratic drug reactions that are specific to this tetracycline.
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PMID:Bioactivation of minocycline to reactive intermediates by myeloperoxidase, horseradish peroxidase, and hepatic microsomes: implications for minocycline-induced lupus and hepatitis. 1950 90

Oxidative stress is increased in systemic lupus erythematosus (SLE), and it contributes to immune system dysregulation, abnormal activation and processing of cell-death signals, autoantibody production and fatal comorbidities. Mitochondrial dysfunction in T cells promotes the release of highly diffusible inflammatory lipid hydroperoxides, which spread oxidative stress to other intracellular organelles and through the bloodstream. Oxidative modification of self antigens triggers autoimmunity, and the degree of such modification of serum proteins shows striking correlation with disease activity and organ damage in SLE. In T cells from patients with SLE and animal models of the disease, glutathione, the main intracellular antioxidant, is depleted and serine/threonine-protein kinase mTOR undergoes redox-dependent activation. In turn, reversal of glutathione depletion by application of its amino acid precursor, N-acetylcysteine, improves disease activity in lupus-prone mice; pilot studies in patients with SLE have yielded positive results that warrant further research. Blocking mTOR activation in T cells could conceivably provide a well-tolerated and inexpensive alternative approach to B-cell blockade and traditional immunosuppressive treatments. Nevertheless, compartmentalized oxidative stress in self-reactive T cells, B cells and phagocytic cells might serve to limit autoimmunity and its inhibition could be detrimental. Antioxidant therapy might also be useful in ameliorating damage caused by other treatments. This Review thus seeks to critically evaluate the complexity of oxidative stress and its relevance to the pathogenesis and treatment of SLE.
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PMID:Oxidative stress in the pathology and treatment of systemic lupus erythematosus. 2410 Apr 61