Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.3.1 (alkaline phosphatase)
47,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Oxmetidine, a new and more potent analogue of the H2 receptor antagonist, cimetidine, was recently withdrawn from clinical trials because of associated hepatotoxicity. We investigated the potential hepatotoxicity of the drug in vitro and in vivo in the rat. In addition, we investigated, in in vitro experiments, the potential hepatoxicity of other gastric acid inhibitory drugs (cimetidine, ranitidine, omeprazole and nolinium bromide). In in vitro experiments, oxmetidine, at various concentrations, was added to isolated hepatocyte incubations and cytotoxicity was assayed by trypan blue exclusion. In in vivo experiments, oxmetidine was administered both i.p. and orally, and hepatotoxicity was assessed by serum biochemical measures (transaminases, alkaline phosphatase, 5' nucleotidase, gamma glutamyl transpeptidase) and liver histopathology. In the in vitro studies, the addition of oxmetidine to the hepatocyte incubations was associated with significant (P less than 0.001) dose and time dependent cytotoxicity. However, the in vivo experiments revealed no significant changes in serum biochemistry and no significant alterations in liver histopathology up to 72 h following the administration three different dosages of oxmetidine. Of the other gastric acid inhibitory drugs, only nolinium bromide was associated with significant (P less than 0.001) in vitro cytotoxicity. Our in vitro observations establish that oxmetidine is cytotoxic to isolated rat hepatocytes and suggest that nolinium bromide be further evaluated for potential hepatotoxicity.
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PMID:Oxmetidine (H2 receptor antagonist) induced cytotoxicity in isolated rat hepatocytes. 290 16

Bovine intestinal alkaline phosphatase was found to hydrolyze inositol phosphates many times faster than the monoester phosphate groups of the polyphosphoinositides. A convenient and sensitive in vitro assay for the Ca2+-dependent polyphosphoinositide phosphodiesterase was devised in which inositol trisphosphate released from exogenous phosphatidylinositol 4,5-bisphosphate was hydrolyzed by alkaline phosphatase. The resulting inorganic phosphate was measured by an automated method after solubilization of the reaction mixture with sodium dodecyl sulfate. The phosphodiesterase was maximally stimulated by combining the known positive effects of cetyltrimethylammonium bromide (at the optimum detergent-to-substrate ratio of 2.3), monovalent cations (0.1 M KCl), and Ca2+ (0.5 mM) with the additional enhancement by Triton X-100 (0.2% w/v). Activities obtained for rat brain homogenates and microsomal and cytosol fractions were 126 +/- 3.8 (17), 110 +/- 5.7 (10), and 252 +/- 15.5 (8) nmol X min-1 X mg protein-1 (mean +/- SE for n determinations), respectively.
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PMID:An enzymatically coupled assay for rat brain polyphosphoinositide phosphodiesterase in an optimized reaction mixture. 300 53

Analogues of bromo-levamisole and guanidine derivatives including cimetidine are examined in vitro in order to investigate their comparative inhibition, towards alkaline phosphatase (ALP) from human liver and diamine-oxidase (DAO) from human placenta. Bromo-levamisole, considered as a potent selective uncompetitive inhibitor of ALP (Ki, 2.8.10(-6) M at pH 10.5) is shown to be a noncompetitive inhibitor of DAO (Ki = 7.10(-4) M). According to the structure-inhibition relationship, the imidazole ring is important for ALP and DAO inhibition. The phenyl ring of bromo-levamisole is required for ALP inhibition but not for DAO inhibition, which is mediated mainly by aminoguanidine or guanidine groups. These results have allowed the selection of cimetidine, an H2-antagonist but also an immunomodulating compound, as inhibitor of these two enzymes. Cimetidine is an uncompetitive inhibitor of ALP (Ki = 3.2.10(-3) M at pH 10.5), and a good inhibitor of DAO (I50 = 3.8.10(-4) M). The Ki of ALP is commonly calculated at pH 10.5, but to study the role of the enzyme at the physiological pH, the inhibition has also been performed at pH 7.4. The Ki values are only slightly affected by this pH variation. So far several compounds, including levamisole, imidazole, theophylline and aminoguanidine are known to possess immunomodulating activities in vivo and/or in vitro and inhibit ALP and/or DAO. Therefore, it seems reasonable to assume that the inhibition of enzymes is involved in the immunomodulating effects of these drugs, when the ranges of active concentrations are similar for these properties.
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PMID:Comparative inhibition of human alkaline phosphatase and diamine oxidase by bromo-levamisole, cimetidine and various derivatives. 314 66

Skeletal growth factor (SGF) activity was extracted from human bone matrix by demineralization and purified under dissociative conditions using hydroxyapatite, HPLC gel-filtration and HPLC reverse-phase chromatography. Human SGF thus purified was characterized chemically and biologically. Purified human SGF stimulated chick embryo bone cell proliferation at picomolar concentrations (half maximum at 2-3 ng/ml) and had little or no activity on other cell types tested (mouse 3T3 and normal rat kidney fibroblasts, embryonic chick intestinal and human placental cells). Human SGF did not displace 125I-labeled epidermal growth factor binding to normal rat kidney cells and did not stimulate normal rat kidney cell colony formation in soft agar. Human SGF activity was sensitive to trypsin, chymotrypsin, papain, dithiothreitol and performic acid but was resistant to heat (upto 70 degrees C), pH (3-10), cyanogen bromide, alkaline phosphatase and neuraminidase and did not bind jack bean concanavalin A or kidney bean lectin. From our chemical and biological studies it appears that human SGF is different from other known polypeptide growth factors: epidermal growth factor, fibroblast growth factor, insulin, insulin-like growth factor-I, platelet-derived growth factor and transforming growth factor.
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PMID:Chemical and biological characterization of low-molecular-weight human skeletal growth factor. 349 Feb 78

The basic nuclear proteins of a fraction of elongating spermatids from human testes and of a fraction of motile spermatozoa from the ejaculate, separated by ion-exchange chromatography, were compared. Analysis by acetic acid-urea polyacrylamide gel electrophoresis (PAGE) showed that, in both fractions, four proteins of lower mobility were coeluted with protamine 1 by 23% guanidinium chloride (GuCl) while protamine 2 alone was eluted by 50% GuCl. Treatment with alkaline phosphatase identified those four proteins as phosphorylated protamines, and cyanogen bromide (CNBr) treatment of the dephosphorylated protamines distinguished them as variants of protamine 2 and not of protamine 1. Thus far, phosphorylated forms of protamine 1 have not been detected in either spermatids or spermatozoa. Those observations indicate that protamine 2 functions in the cycle of phosphorylation-dephosphorylation, which is essential to the process of sperm chromatin condensation, while the role of protamine 1 in human spermiogenesis is not yet defined. The presence of phosphorylated protamine in motile, presumably mature spermatozoa appears to be characteristic of human sperm but not of the sperm of other mammals and is probably the basis for the heterogeneity of chromatin condensation frequently observed in human spermatozoa.
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PMID:Phosphorylation state of protamines 1 and 2 in human spermatids and spermatozoa. 350 69

Male Fischer 344 rats were used to investigate the hepatic effects of exposure to halothane under normoxic conditions (FIO2 = 0.21) in isoniazid-treated rats. Animals were treated with saline or isoniazid (50 mg/kg) for 7 days and then were exposed to either 1% halothane or air for 2 hr. One-half of the rats from each treatment and exposure group were killed 24 hr postexposure; the remaining were killed 4 days postexposure. Twenty-four hours following halothane exposure, serum transaminase levels were significantly elevated in isoniazid- compared with saline-treated rats (i.e., aspartate aminotransferase = twofold; alanine aminotransferase = seven-fold). Cholesterol levels were significantly depressed by halothane exposure in both saline- and isoniazid-treated rats. Other serum parameters indicative of hepatic and renal function were not different: alkaline phosphatase, total protein, total bilirubin, hematocrit, uric acid, creatinine, urea nitrogen, Na+, K+, Ca2+, and inorganic phosphate. Neither saline-treated nor isoniazid-treated rats exposed to air exhibited histologic evidence of hepatic damage. Halothane-exposed rats, however, showed a circumscribed disruption of cellular morphology. The most severe lesions were observed with isoniazid-treated animals with extensive pericentral hepatocellular necrosis and infiltration by leucocytes and Kupffer cells. Serum concentrations of two products of the oxidative metabolism of halothane, trifluoroacetic acid and bromide, were significantly elevated in isoniazid- compared with saline-treated rats. Serum levels of fluoride, a product of reductive metabolism, were not different. These results strongly suggest that hepatic injury following halothane administration can be produced by intermediates of oxidative metabolism.
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PMID:Halothane hepatotoxicity in Fischer 344 rats pretreated with isoniazid. 356 16

The major scrapie prion protein, designated PrP 27-30, exhibited both charge and size heterogeneity after purification from infected hamster brains. Eight or more discrete charge isomers of PrP 27-30 with isoelectric points ranging from approximately pH 4.6 to 7.9 were found by using non-equilibrium pH gradient electrophoresis in the first dimension followed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis in the second dimension. The charge isomers were detected by silver staining as well as by radioiodination. The procedures used to disaggregate PrP 27-30 before electrophoresis in the first dimension do not appear to be responsible for the charge heterogeneity. However, heating PrP 27-30 to 100 degrees C for 15 min in 0.1 N NaOH or 0.1 N HCl resulted in modification of the protein and alteration of its electrophoretic pattern. A PrP 27-30 fragment (molecular weight, 17,100 to 21,900) obtained by cyanogen bromide cleavage also exhibited charge and size heterogeneity. Periodic acid-Schiff staining of PrP 27-30 electrophoresed into sodium dodecyl sulfate-polyacrylamide gels demonstrated that carbohydrate residues are attached to the protein. Digestion of PrP 27-30 with neuraminidase and endo-beta-N-acetylglucosaminidase H resulted in significant changes in the isoelectric pH of PrP 27-30 isomers, whereas digestion with alkaline phosphatase had no effect. Our results demonstrate that PrP 27-30 is a sialoglycoprotein; this is consistent with several properties of this protein and of the scrapie prion.
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PMID:Scrapie PrP 27-30 is a sialoglycoprotein. 391 76

Two in vitro cytotoxicity procedures, the measurement of cell-membrane integrity using fluorescein diacetate and ethidium bromide, and the quantitation of the release of a cell-membrane-bound enzyme, alkaline phosphatase, were used to assess the cytotoxicity of a range of cationic, anionic and nonionic detergents. The in vitro results were compared with the in vivo irritancy of these compounds in the rabbit eye. Although in general the decreasing order of potency of cationic, anionic and nonionic detergents was similar in vivo and in vitro, there were some apparent anomalies which may be due to the differing penetration characteristics of the detergents, as indicated by electrical impedance measurements of the isolated cornea. The study was extended to an examination of the cytotoxicity of a range of completely soluble, detergent-based formulations in a suspension culture of mouse fibroblasts. In this case the in vitro results correlated more closely with those from the in vivo tests.
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PMID:An in vitro cytotoxicity test to predict the ocular irritation potential of detergents and detergent products. 404 73

The localization of alkaline phosphatase in the specific granules of rabbit polymorphonuclear leukocytes was investigated. The results obtained suggest very strongly that alkaline phosphatase is a component of the granule membrane. The enzyme remains attached to the membrane upon disruption of the granules by the use of detergents or by hypotonic shock and subsequent extraction with sodium sulfate, and can be isolated together with fragments of the granule membrane by isopycnic equilibration. Treatment of the granules with high amounts of Triton-X-100, sodium deoxycholate, or hexadecyltrimethylammonium bromide releases the enzyme in soluble form. In polymorphonuclear leukocyte homogenates, lysis of the granules is needed in order to render alkaline phosphatase fully accessible to substrates. This suggests that the catalytic site of the enzyme is exposed at the inner face of the granule membrane.
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PMID:Association of the alkaline phosphatase of rabbit polymorphonuclear leukocytes with the membrane of the specific granules. 476 36

The ability of eight stripping agents to solubilize five marker enzymes from rat renal brush border membranes isolated by three different preparative methods was examined. Protein and enzyme activities - alkaline phosphatase (APase), L-leucine aminopeptidase (LAPase), gamma-glutamyl transpeptidase (GGTase), gamma-glutamyl hydrolase (GGHase) and maltase - solubilized by the treatments were expressed as percent of total activity recovered in excess of control values. The relative enzyme activity and the solubilization factor were determined for each marker enzyme in every treated sample and the treatments with the eight agents compared. Trypsin treatment released > 80% of LAPase and < 10% of total membrane protein. Papain treatment released only 16--23% of total membrane protein but most of the enzyme activities except APase. Neuraminidase had no solubilizing effect. 4--10% of total membrane protein was solubilized by LiCl treatment but no marker enzyme activities were released. Less total membrane protein was released by treatment with proteolytic enzymes or LiCl than with the detergents Triton X-100, hexadecyltrimethylammonium bromide, sodium deoxycholate, and sodium dodecylsulfate. APase activity was the least readily solubilized. Correlating the degree of solubilization for five marker enzymes with the types of stripping agents used and with the appearance of the membrane surface when examined by electron microscopy led to the suggestion that LAPase, GGTase, GGHase and maltase molecules are part of an interwoven surface layer of membrane proteins which can be disrupted by transamidation and transesterification reactions. APase appears to be more strongly associated with the intact lipid matrix than the bulk of the membrane protein.
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PMID:Ease of solubilization of five marker enzymes in three preparations of rat renal brush border membranes. 610 74


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