Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mechanisms of proton transport were investigated in planar phospholipid bilayer membranes exposed to aspirin (acetylsalicylic acid), acetaminophen (4-acetamidophenol), benzoic acid and three aspirin metabolites (salicylic acid, gentisic acid and salicyluric acid). The objectives were to characterize the conductances and permeabilities of these weak acids in lipid bilayer membranes and then predict their effects on mitochondrial membranes. Of the compounds tested only aspirin, benzoate and salicylate caused significant increases in membrane conductance. The conductance was due mainly to proton current at low pH and to weak acid anion current at neutral pH. Analysis of the concentration and pH dependence suggests that these weak acids act as HA-2-type proton carriers when pH approximately pK and as lipid soluble anions at neutral pH. Salicylate is much more potent than aspirin and benzoate because salicylate contains an internal hydrogen bond which delocalizes the negative charge and increases the permeability of the anion. Model calculations for mitochondria suggest that salicylate causes net H+ uptake by a cyclic process of HA influx and A- efflux. This model can explain the salicylate-induced uncoupling and swelling observed in isolated mitochondria. Since ingested aspirin breaks down rapidly to form salicylate, these results may clarify the mechanisms of aspirin toxicity in humans. The results may also help to explain why the ingestion of aspirin but not acetaminophen is associated with Reye's syndrome, a disease characterized by impaired energy metabolism and mitochondrial swelling.
Mol Cell Biochem 1992 Sep 08
PMID:Aspirin, acetaminophen and proton transport through phospholipid bilayers and mitochondrial membranes. 133 28

Possible effects of single point mutations on the ligand-binding capabilities of human serum albumin (Alb) were investigated by studying the interactions between the strongly bound drugs warfarin, salicylate, and diazepam and five structurally characterized genetic variants of the protein. Equilibrium dialysis data, obtained with the variants and normal serum Alb, revealed pronounced reductions in high affinity binding of all three ligands to Alb Canterbury (313 Lys----Asn) and to Alb Parklands (365 Asp----His). By contrast, unchanged binding of the drugs was found in the case of Alb Verona (570 Glu----Lys). Different effects on binding were observed for the other two variants. Salicylate was the only drug bound with a lower affinity to Alb Niigata (269 Asp----Gly), whereas binding of both salicylate and diazepam to Alb Roma (321 Glu----Lys) were moderately reduced. In about half of the cases of diminished binding, the primary association constant was reduced by 1 order of magnitude, giving rise to an increase in the unbound fraction of the drugs of 500% or more at therapeutically relevant molar ratios of drug and protein. Changes in protein charge seem to be of only minor importance for reduced binding. More likely, conformational changes in the 313-365 region of the proteins are the main cause for diminished binding of these diverse ligands, which probably have different high affinity binding sites. The specific reduction in salicylate binding after modification of residue 269 may be due to conformational changes at or close to the salicylate binding site.
Mol Pharmacol 1990 Feb
PMID:Binding of warfarin, salicylate, and diazepam to genetic variants of human serum albumin with known mutations. 230 52

Salicylate is a precursor of pyochelin in Pseudomonas aeruginosa and both compounds display siderophore activity. To elucidate the salicylate biosynthetic pathway, we have cloned and sequenced a chromosomal region of P. aeruginosa PAO1 containing two adjacent genes, designated pchB and pchA, which are necessary for salicylate formation. The pchA gene encodes a protein of 52 kDa with extensive similarity to the chorismate-utilizing enzymes isochorismate synthase, anthranilate synthase (component I) and p-aminobenzoate synthase (component I), whereas the 11 kDa protein encoded by pchB does not show significant similarity with other proteins. The pchB stop codon overlaps the presumed pchA start codon. Expression of the pchA gene in P. aeruginosa appears to depend on the transcription and translation of the upstream pchB gene. The pchBA genes are the first salicylate biosynthetic genes to be reported. Salicylate formation was demonstrated in an Escherichia coli entC mutant lacking isochorismate synthase when this strain expressed both the pchBA genes, but not when it expressed pchB alone. By contrast, an entB mutant of E. coli blocked in the conversion of isochorismate to 2,3-dihydro-2,3-dihydroxybenzoate formed salicylate when transformed with a pchB expression construct. Salicylate formation could also be demonstrated in vitro when chorismate was incubated with a crude extract of P. aeruginosa containing overproduced PchA and PchB proteins; salicylate and pyruvate were formed in equimolar amounts. Furthermore, salicylate-forming activity could be detected in extracts from a P. aeruginosa pyoverdin-negative mutant when grown under iron limitation, but not with iron excess. Our results are consistent with a pathway leading from chorismate to isochorismate and then to salicylate plus pyruvate, catalyzed consecutively by the iron-repressible PchA and PchB proteins in P. aeruginosa.
Mol Gen Genet 1995 Nov 15
PMID:Structural genes for salicylate biosynthesis from chorismate in Pseudomonas aeruginosa. 750 Sep 44

Salicylate is widely used as a stable trap for the highly reactive hydroxyl radical. The purpose of this study was to determine whether the addition of salicylate to hearts subjected to ischemia and reperfusion was able to prevent some injury. Salicylate was able to inhibit mitochondrial damage, and preserved ascorbate and alpha-tocopherol depletion due to ischemia/reperfusion in rat hearts. It did not prevent the elevation of low molecular weight iron. We conclude that salicylate functions as an antioxidant and afforded protection against ischemia and reperfusion.
Res Commun Mol Pathol Pharmacol 1994 Dec
PMID:Salicylate in the perfusate during ischemia/reperfusion prevented mitochondrial injury. 771 5

Infection of tobacco by tobacco mosaic virus (TMV) induces coordinate expression of genes encoding acidic and basic beta-1,3-glucanase isoforms. These genes are differentially expressed in response to other treatments. Salicylate treatment induces acidic glucanase mRNA to a higher level than basic glucanase mRNA. Ethylene treatment and wounding strongly induce the basic glucanase genes but have little effect on genes encoding the acidic isoforms. Furthermore, the basic glucanase genes are constitutively expressed in roots and lower leaves of healthy plants, whereas the acidic glucanase genes are not. In order to investigate how these expression patterns are established, we fused promoter regions of an acidic and a basic glucanase gene to the beta-glucuronidase (GUS) reporter gene and examined expression of these constructs in transgenic tobacco plants. A fragment of 1750 bp and two 5'-truncated fragments of 650 bp and 300 bp of the acidic glucanase promoter were tested for induction of GUS gene expression after salicylate treatment and TMV infection. Upstream sequences of 1750 bp and 650 bp were sufficient for induction of the reporter gene by salicylate treatment and TMV infection, but the activity of the 300 bp fragment was strongly reduced. The results suggest that the 1750 bp upstream sequence of the acidic glucanase gene contains multiple regulatory elements. For the basic glucanase promoter it is shown that 1476 bp of upstream sequences were able to drive expression in response to TMV infection and ethylene treatment, but no response was found to incision wounding. Furthermore, high GUS activity was found in lower leaves and roots of healthy transgenic plants, carrying the 1476 bp basic glucanase promoter/GUS construct. When the promoter was truncated up to position -446 all activity was lost, indicating that the region between -1476 and -446 of the basic glucanase promoter is necessary for organ-specific and developmentally regulated expression as well as for induced expression in response to infection and other stress treatments.
Plant Mol Biol 1993 Feb
PMID:Analysis of regulatory elements involved in stress-induced and organ-specific expression of tobacco acidic and basic beta-1,3-glucanase genes. 844 40

Bioactivation of phenytoin and related teratogens by peroxidases such as prostaglandin H synthase (PHS) may initiate hydroxyl radical (.OH) formation that is teratogenic. Salicylate is hydroxylated by .OH at the third and fifth carbon atoms, forming 2,3- and 2,5-dihydroxybenzoic acids (DHBA). In vivo salicylate metabolism produces only the 2,5-isomer, so 2,3-DHBA formation may reflect .OH production. In the present study, we validated the salicylate assay using the known .OH generator paraquat and evaluated .OH production by phenytoin. Female CD-1 mice were treated with paraquat (30 mg/kg, intraperitoneally) given 30 min after acetylsalicylic acid (ASA) (200 mg/kg, intraperitoneally). Blood was collected at 5, 15, and 30 min and 1 and 2 hr after paraquat, and plasma was analyzed for DHBA isomers and glucuronide conjugates by high performance liquid chromatography with electrochemical detection. Paraquat increased 2,3-DHBA formation 19.2-fold, with substantial inter-individual variability in the time of maximal formation (p = 0.0001). The 2,3-DHBA glucuronide conjugates in vivo and in hepatic microsomal studies amounted to approximately 11% and 0.43%, respectively, of total 2,3-DHBA equivalents. To investigate putative .OH production initiated via PHS-catalyzed phenytoin bioactivation, ASA was given 30 min before phenytoin (65 or 100 mg/kg, intraperitoneally), resulting in respective 7.6-fold (p = 0.02) and 14.2-fold (p = 0.003) increases in phenytoin-initiated maximal 2,3-DHBA formation. Maximal 2,3-DHBA formation was 2.1-fold higher when ASA was administered after rather than before the same dose (65 mg/kg) of phenytoin (p = 0.03), indicating ASA inhibition of PHS-catalyzed phenytoin bioactivation. Urinary analysis was much less sensitive, and the 2,5-isomer reflected enzymatic rather than .OH-mediated hydroxylation. The paraquat studies demonstrate the importance of timing in accurately quantifying 2,3-DHBA formation and suggest that glucuronidation does not interfere. The substantial, dose-dependent initiation of 2,3-DHBA formation by phenytoin, and its inhibition by ASA, provide the first in vivo evidence that PHS-dependent .OH formation could contribute to the molecular mechanism of phenytoin teratogenesis.
Mol Pharmacol 1996 Jan
PMID:Phenytoin-initiated hydroxyl radical formation: characterization by enhanced salicylate hydroxylation. 856 4

Menadione (vitamin K-3,2-methyl-1,4-naphthoquinone), a redox cycling reagent, generates reactive oxygen intermediates and causes oxidative injury. The addition of menadione to Hep G2 cells produced a time- and concentration-dependent loss of cell viability. Preincubation of Hep G2 cells with low, nontoxic concentrations of menadione increased the viability of the cells against toxic doses of menadione or H2O2. Maximum protection was found with menadione concentrations of approximately 3 microM and preincubation times of approximately 45 min. This protective effect could be blocked by the protein synthesis inhibitor cycloheximide and by a variety of antioxidants. The transcription factor nuclear factor-kappaF (NF-kappaB) is known to be activated by many compounds, including reactive oxygen intermediates. Menadione activated NF-kappaB as determined by electrophoretic mobility shift assays. This activation was prevented by the same antioxidants that blocked protection against cytotoxicity produced by preincubation with menadione. Anti-p50 IgG prevented the menadione-stimulated binding of NF-kappaB to the oligonucleotide probe, whereas anti-p65 IgG produced a supershift of the NF-kappaB/oligonucleotide complex. Salicylate prevented the activation of NF-kappaB by menadione, and under these conditions, salicylate potentiated the cytotoxicity of menadione or H2O2. Transfection with a plasmid containing cDNA encoding mouse IkappaBbeta, an inhibitor of NF-kappaB, resulted in increased toxicity by menadione. Furthermore, when protein kinase C was down-regulated by prolonged treatment with active phorbol ester (phorbol-12-myristate-13-acetate), the Hep G2 cells became more sensitive to menadione treatment. However, short term treatment with PMA, which activated NF-kappaB, resulted in protection against menadione cytotoxicity. Menadione cytotoxicity was enhanced when the Hep G2 cells were depleted of GSH. An increased level of GSH was observed after menadione pretreatment; this increase was blocked by salicylate, thereby linking the GSH increase to activation of NF-kappaB by menadione. The results of the current study suggest that menadione pretreatment protects Hep G2 cells from oxidative injury through an NF-kappaB-related mechanism, which may involve, in part, increased production of GSH.
Mol Pharmacol 1997 Oct
PMID:Menadione cytotoxicity to Hep G2 cells and protection by activation of nuclear factor-kappaB. 938 28

Transient ischemia has been shown to impair endothelium-dependent, but not endothelium-independent, coronary vasodilation, indicating selective endothelial dysfunction. Here a hypothesis was tested that agonist mediated activation of protein kinase C (PKC) and the related overproduction of the oxidative species contribute to the mechanism of the endothelial dysfunction. Perfused guinea-pig hearts were subjected either to 30 min global ischemia/30 min reperfusion or to 30 min aerobic perfusion with a PKC activator, phorbol ester (1 n M, PMA). Coronary flow responses to a bolus of acetylcholine (ACh) and sodium nitroprusside (SNP) were used as measures of endothelium-dependent and endothelium-independent vascular function, respectively. Salicylate hydroxylation was used as the assay for the myocardial hydroxyl radical (.OH) formation. Both ischemia/reperfusion and PMA impaired the ACh response and augmented the myocardial.OH production. The effect of ischemia/reperfusion on the ACh response: (i) was fully prevented by a PKC inhibitor, chelerythrine (2microM) and a mixed endothelin blocker, bosentan (20microM); (ii) was partially prevented by an endothelin converting-enzyme inhibitor, phosphoramidon (40microM), and superoxide dismutase (150-500 U/ml, SOD) and (iii) was affected neither by catalase (600 U/ml) nor by losartan (20microM) and captopril (250microM), nor by prazosin (10microM). SOD, but not bosentan, partially prevented the effect of PMA on the ACh response. None of the interventions studied affected the SNP response. The reperfusion-induced.OH release was attenuated by chelerythrine and bosentan, was not affected by prazosin and was increased by SOD. These results implicate the following sequence of events in the mechanism of the post-ischemic endothelial dysfunction: ischemia/reperfusion, endothelin-induced PKC activation, increased production of superoxide and/or some of its toxic metabolite, damage to the endothelium and endothelial dysfunction. The results argue against the contribution of angiotensin II, adrenergicalpha(1)-receptors and kinins in the mechanism of the post-ischemic endothelial dysfunction in guinea-pig hearts.
J Mol Cell Cardiol 2000 Feb
PMID:The role of endothelin, protein kinase C and free radicals in the mechanism of the post-ischemic endothelial dysfunction in guinea-pig hearts. 1072 5

Sodium salicylate and acetylsalicylic acid are drugs used as anti-inflammatory agents. Salicylate prevents nuclear factor-kappa B activation and can cause apoptosis. However, salicylate, a substrate of CYP2E1, is also an antioxidant and can scavenge reactive oxygen species. Experiments were carried out to evaluate whether salicylate can modulate CYP2E1-dependent toxicity. Addition of a polyunsaturated fatty acid such as arachidonic acid (AA) to HepG2 cells resulted in loss of cell viability, especially in cells expressing CYP2E1 (E47 cells). Toxicity was enhanced by the addition of 1 to 10 mM salicylate to the E47 cells but not to control HepG2 cells or HepG2 cells expressing CYP3A4. Salicylate alone was not toxic, and the enhanced toxicity by AA in the presence of salicylate was prevented by diallyl sulfide, a CYP2E1 inhibitor, and by the antioxidant (+/-)6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid. Salicylate potentiated AA-induced lipid peroxidation in the E47 cells, a reaction blocked by diallyl sulfide. CYP2E1 levels were elevated by salicylate at concentrations (<5 mM), which did not increase CYP2E1 mRNA levels. This increase was associated with a decrease of CYP2E1 turnover by salicylate in the presence of cycloheximide. Salicylate also potentiated AA toxicity in hepatocytes isolated from pyrazole treated rats with high levels of CYP2E1 and from saline controls. In view of the potential role of CYP2E1 in contributing to alcohol-induced oxidative stress and liver injury, the potentiation of CYP2E1-dependent toxicity and the elevation of CYP2E1 levels by salicylate may be of clinical significance and merit caution in the use of salicylate and salicylate precursors such as acetylsalicylic acid with certain other drugs.
Mol Pharmacol 2001 Apr
PMID:Sodium salicylate increases CYP2E1 levels and enhances arachidonic acid toxicity in HepG2 cells and cultured rat hepatocytes. 1125 24

Salicylate and jasmonates are two different types of plant hormone that play critical roles in plant defense responses against insect herbivores and microbial pathogens, through activating defense genes. These two natural products have been shown to have similar activities in animal cells: the compounds are able to induce cell cycle arrest or apoptosis in a variety of human cancer cells including those of colon, prostate, breast, and leukemia, suggesting the chemicals may potentially be a novel class of anti-cancer drugs. Since sodium salicylate can induce the heat shock response in animals, we examined the effects of jasmonates on the heat shock response in C6 glioma cells. Here, we show that brief exposure to methyl jasmonate (MeJA), but not to jasmonic acid, induces heat shock protein 72 (HSP72), but not HSP73 and HSP90, via heat shock factor I (HSF1) activation in C6 glioma cells without affecting cell viability. Intracellular H2O2 and O2-, and mitochondrial ROS were prominently increased in response to 5 mM MeJA in C6 cells. MeJA-induced HSP72 expression, HSF1 DNA binding, and human HSP70 promoter-driven CAT activity were prevented by N-acetyl-L-cysteine (a general antioxidant), catalase (a specific antioxidant for H2O2), and sodium formate (an inhibitor of OH.), but not by Rac1 dominant negative mutant Rac1N17 and diphenyleneiodonium (a NADPH oxidase inhibitor), indicating that MeJA induces HSP72 expression though HSF1 that is activated via Rac1-NADPH oxidase-independent ROS production pathway. These results suggest that the plant stress hormones share the ability to induce heat shock response in animal cells.
Int J Mol Med 2005 Nov
PMID:Induction of heat shock protein 72 in C6 glioma cells by methyl jasmonate through ROS-dependent heat shock factor 1 activation. 1621 Dec 52


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