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)

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

MDL-899 is new phthalazine derivative which has been developed as a substitute for hydralazine, which has several undesirable effects, in the treatment of hypertension. The effects of MDL-899 on human lymphocyte functions are analyzed. This drug inhibited in a dose-related fashion the blastogenesis of lymphocytes upon PHA and Con A activation and down-regulated the activation of allogeneic mixed lymphocyte reactions (MLR). On the contrary the drug enhanced the activation of autologous MLR of non T/T type. This effect was five times higher on cells which carried the HLA DR 4 phenotype. The above reported observations suggest that MDL-899, as well as hydralazine, affects the in vitro responsiveness of human lymphocytes mostly in subjects with HLA-DR 4 phenotype. Whether the impact of MDL-899 on immune function gives rise to a lupus like syndrome is not known. For this reason further studies are warranted to assess its long-term in vivo effects.
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PMID:The effects of a new phthalazine derivative (MDL 899) on human lymphocyte functions. 294 87

1-Hydrazinophthalazine [hydralazine (HDZ)] is a hydrazine derivative that is a direct acting vasodilator effective in the treatment of essential hypertension. HDZ is biotransformed by the phase II conjugation enzyme N-acetyltransferase (NAT) forming acetyl HDZ, which spontaneously cyclized to the stable product 3-methyl-s-triazolo- [3,4-alpha]-phthalazine (MTP). Therapeutic use of HDZ has resulted in adverse side effects, specifically a drug-induced systemic lupus erythematosus. Slow acetylators are more likely than rapid acetylators to develop this toxicity. Bacteria expressing different levels of NAT were used to test the hypothesis that acetylation of HDZ decreases its mutagenic potential. The variation in NAT activities was confirmed by incubating bacterial cultures with HDZ, and the formation of MTP was monitored by HPLC. At 1.0 mg/ml HDZ, YG1029 (NAT overexpresser) produced 5.3 times the amount of MTP as TA100 (normal NAT expresser), and this production was linear for 20 hr. In the Salmonella mutagenesis assay, HDZ produced a dose- and strain-dependent increase in the number of revertants observed. Exposure to 4 mg HDZ/plate resulted in 1000 revertants in the overexpressing strain, YG1029, whereas both TA100 and TA100/1,8DNP6, which express normal levels and lack the NAT protein respectively, produced 1600 revertants. Colony hybridization analysis using probes for each of the six possible TA100 reverting mutations was performed to determine the nature of the mutations. The G:C to T:A transversion was the only mutation whose frequency was increased significantly by HDZ. Fifty-four percent of the induced vs. 25% of the spontaneous mutations were C to A transversions.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Acetylation and its role in the mutagenicity of the antihypertensive agent hydralazine. 758 31

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