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)

Sprague-Dawley rats were dosed by gavage daily for 28 days with 5, 15, or 50 mg/kg of N-(all-trans-retinoyl)-DL-leucine (RL), N-(all-trans-retinoyl)glycine (RG), or all-trans-retinoic acid (RA). On the basis of mortality incidence, fracture incidence, body weight, and histopathologic effects, RG was slightly to moderately less toxic than RA, and RL was significantly less toxic than RA or RG. Doses that had no effect on weight loss and produced no bone fractures were approximately 5 and 15 mg/kg/day for RA administered to males or females, respectively; greater than 15 mg/kg/day for RG administered to males or females; and greater than 50 mg/kg/day for RL administered to males or females. At these doses, RA and RG produced effects, detectable at the microscopic level, of lymphoid hyperplasia and hematopoietic cell proliferation in the spleen, lymphoid hyperplasia in lymph nodes, necrosis of the cortex of the thymus, hypertrophy of the zona fasciculata of the adrenal, a periportal pattern of cytoplasmic vacuolization in hepatocytes, hematopoietic cell proliferation in the liver, epithelial hyperplasia and subacute inflammation in the forestomach, and osteodystrophy. Serological alterations consisted of reduced serum albumin levels and elevated levels of triglycerides and alkaline phosphatase. For RL, similar microscopic effects, dependent on dose level and sex, were observed in spleen, thymus, adrenal, and liver. In vitro, RL was as active as RA in potentiating pokeweed mitogen-induced lymphocyte proliferation; RG was inactive. This study indicates that, relative to RA and RG, RL has less toxicity but similar immunological effects. Since RL and RG expressed little or no binding affinity for cellular RA-binding protein, the immunological effects of these retinoids may be expressed by mechanisms not linked to this protein.
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PMID:Toxicologic and immunologic evaluations of N-(all-trans-retinoyl)-DL-leucine and N-(all-trans-retinoyl)glycine. 319 15

A monoclonal antibody to the non-thymosin alpha 1 overlapping sequence of parathymosin alpha was used to develop a micro ELISA to measure parathymosin alpha. Parathymosin alpha levels were measurable in both mouse tissue extracts and in human adult and cord serum. To measure parathymosin alpha, a 40% ammonium sulfate precipitated monoclonal antibody specific for the parathymosin alpha fragment was preincubated with the parathymosin alpha fragment or samples for 4 hours at 4 degrees C, incubated an additional 24 hours in microtiter plates coated with the parathymosin alpha fragment and then assayed by the biotin-avidin-alkaline phosphatase method. Using the assay, parathymosin alpha could be measured over a range of 5 to 630 ng/ml and cross-reactivity with thymosin alpha 1 was not observed. The parathymosin alpha level was 400 +/- 140 (mean +/- SD) ng/ml in normal human sera (n = 12) and 150 +/- 80 ng/ml in cord sera (n = 12). The concentration of parathymosin alpha was highest in tissue extracts of mouse liver (153 +/- 40 micrograms parathymosin alpha per g of tissue), kidney (125 +/- 33), and lung (105 +/- 38). Levels were lowest in thymus (81 +/- 20), spleen (83 +/- 23), and brain (71 +/- 23).
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PMID:Micro ELISA for measurement of parathymosin alpha utilizing a monoclonal antibody. 325 92

The progression of aflatoxicosis was evaluated in growing crossbred barrows given 0, 1, 2, 3, or 4 mg of aflatoxin (AF)/kg of feed for 28 days (6 to 10 weeks of age). On day 28, pigs were euthanatized and necropsied, and tissues were removed for histologic examination. Body weight gains were decreased in barrows fed 2 mg of AF/kg after 7 days and in barrows fed 1 mg of AF/Kg after 14 days. By 28 days, all barrows fed AF had decreased body weights and weight gains. Compared with decreased in all barrows fed AF. Neither liver weights nor bone ash values were altered, although liver lipid values were increased in barrows fed AF. Serum aspartate transaminase, gamma-glutamyl transferase, and alkaline phosphatase activities were increased in barrows fed AF, whereas creatine kinase activity was decreased. Aflatoxin diets resulted in decreases in serum concentrations of urea nitrogen, phosphorus, cholesterol, albumin, and total protein. Histologic alterations in liver included interlobular fibrosis, periportal lipidosis, bile duct hyperplasia, and periportal lymphocytic infiltration. Lymphocytes in the thymus were depleted, and numbers of granulocytic cells in the bone marrow were reduced. The frequency and severity of lesions increased with increased doses of AF.
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PMID:Progression of aflatoxicosis in growing barrows. 337 6

1. Seven subfractions of histone H1 have been isolated and purified from larvae of Chironomus thummi (Diptera). They have been denominated I-1, II-1, II-2, II-3, III-1, III-2, and III-3, according to the order of migration in two steps of preparative electrophoresis. 2. The amino acid compositions are similar to those of other H1 histones. Subfractions I-1 and II-1 were found to contain one methionine and two tyrosine residues, II-2 contained two methionine and three tyrosine residues, and III-1 one methionine and three tyrosine residues. The other subfractions contained one or two methionine and two or three tyrosine residues. For subfractions I-1 and II-1 a chain length of about 252 amino acids was estimated. 3. Peptide pattern analyses after chemical cleavage at the methionine and tyrosine residues, and enzymatic cleavage with thrombin and chymotrypsin, respectively, showed that all subfractions have different individual primary structures. A comparison of peptide sizes and of the positions in the peptide patterns of epitopes recognized by monoclonal antibodies was made to check whether some of the subfractions could arise by proteolytic degradation of others. This possibility can be excluded for five of the subfractions and is very improbable for the two others. Treatment of C. thummi H1 with alkaline phosphatase did not change the pattern of subfractions, while the phosphorylated subfraction of histone H2A disappeared after this treatment. Most and very probably all subfractions are thus H1 sequence variants. 4. Inbred strains and individual larvae of C. thummi were found to comprise all seven variants. The H1 heterogeneity can therefore not be due to allelic polymorphism. Salivary gland nuclei were found to contain variant I-1 and at least some of the other variants. 5. H1 from Drosophila melanogaster and from calf thymus were used as reference molecules in all cleavage experiments and yielded the peptide patterns expected from the sequence. The comparison discriminates the group of C. thummi H1 histones clearly from Drosophila and calf thymus H1. Limited trypsin digestion yielded a protected peptide of uniform size in six of the seven variants which was considerably smaller than the protected central domain of calf thymus H1. 6. Two other species of Chironomidae, C. pallidivittatus and Glyptotendipes barbipes were found to contain five and three H1 subfractions, respectively.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Histone H1 heterogeneity in the midge, Chironomus thummi. Structural comparison of the H1 variants in an organism where their intrachromosomal localization is possible. 341 67

There are at least three alkaline phosphatase (AP) isoenzymes in man: a heat-stable placental enzyme (PLAP), a less heat-stable intestinal form (IAP), and the very heat-labile AP enriched in liver, bone and kidney. In addition to these enzymes, there is a heat-stable activity in the thymus and testis that is similar but not identical to the PLAP (the PLAP-like enzyme). Previous work has demonstrated a close structural relatedness among the IAP, PLAP and PLAP-like enzymes. Thus, it is possible that there are three human genes encoding heat-stable AP enzymes. To test this hypothesis, we have used a PLAP cDNA clone to screen a human genomic library cloned into the phage vector lambda EMBL-3. Three sets of clones were isolated, each bearing a distinct coding region homologous to the PLAP cDNA probe. Nucleotide sequence analysis of the 5' ends of these genes allowed comparison of their derived peptide sequences and positive identification of two of the genes. One of the genes encodes the PLAP (the PLAP-1 gene), another encodes the IAP, and a third closely resembles the PLAP-1 gene, but is distinct from it (the PLAP-2 gene). The PLAP-2 gene is highly homologous (greater than 95%) with the PLAP-1 except in the first exon, where sequences encoding the hydrophobic signal peptide are nearly identical with the same region of the IAP gene. These results demonstrate the existence of a small family of PLAP-related genes which is the result of at least two duplication events during the descent of man.
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PMID:Two gene duplication events in the evolution of the human heat-stable alkaline phosphatases. 344 2

The formation of benzo[a]pyrene (BP)-DNA adducts was studied in vitro in the presence of microsomes prepared from the isolated labyrinth zone of the rat placenta, the hematopoietic erythroblast cells of the fetal liver, the fetal liver, as well as the maternal liver. Pregnant rats received beta-naphthoflavone (beta NF; 15 mg/kg, i.p.) on day 17 gestation. One day later, placentae, fetal and maternal livers were obtained and hematopoietic erythroblast cells were separated from hepatocytes in the fetal livers. The respective microsomal fractions were incubated in the presence of calf thymus DNA, NADPH-regenerating system and [3H]BP (300 microCi) at 37 degrees C for 30 min. Following beta NF pretreatment, the levels of covalent binding (pmol/mg DNA/mg microsomal protein) for maternal liver, fetal liver, placenta and erythroblast cells were: 28.4, 2.4, 0.31 and 3.9, respectively, with the hematopoietic erythroblast cells being the most active among fetal tissue preparations. The extent of transplacental induction compared to control was greatest in the hematopoietic cells (18-fold) followed by fetal liver (16-fold) and labyrinth zone (5-fold). Further experiments characterized the BP-DNA adducts formed by induced microsomes. DNA was isolated, purified and digested sequentially with DNase I, snake venom phosphodiesterase type II and alkaline phosphatase type III. The deoxynucleoside-BP adducts were purified on a Sephadex LH-20 column and then separated on HPLC and the adducts were quantitated radiometrically. Seven distinct adducts were separated on HPLC and named A-G in order of elution. Adduct B was prominent in all preparations (22-55% total radioactivity). The adduct profile and retention time for peak B is similar to that reported for the adduct formed by microsomal activation of 9-hydroxy BP. Peak D constituted a major fraction (19%) in maternal liver profiles in comparison with the three fetal tissue preparations (8%). In subsequent experiments, peak D was shown to be derived from reaction of (+/-)7 beta,8 alpha-dihydroxy-9 alpha,10 alpha-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (BPDE) with DNA. Peak C was unique to erythroblast cell and labyrinth profiles, while peak G was specific for maternal liver and fetal liver profiles. These results demonstrate that fetal liver and its hematopoietic cells are significant sites of BP bioactivation which may contribute to the fetal toxicity of polyaromatic hydrocarbons.
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PMID:Formation of benzo[a]pyrene-DNA adducts by microsomal enzymes: comparison of maternal and fetal liver, fetal hematopoietic cells and placenta. 356 91

Clarified slurry oil (CSO), the heavy residual fraction from the fluidized catalytic cracker, was applied to the shaven backs of groups of 10 male and 10 female Sprague-Dawley rats 5 days/week for 13 weeks at doses of 8, 30, 125, or 500 mg/kg/day, and to another group for 2 weeks at doses of 2000 mg/kg/day. The rats were fitted with cardboard Elizabethan collars to minimize the ingestion of the test material, which was applied undiluted and remained uncovered on the skin. A similar group of rats served as controls; they were treated in the same manner except that no CSO was applied to their skin. There was a dose-related mortality and depression of body weight gain in the rats treated with CSO at doses of 30 mg/kg/day or greater; none of the rats dosed at 2000 mg/kg/day survived more than 2 weeks. The primary target organs of CSO toxicity were the liver, thymus, and bone marrow. The effects on the liver included increased weight (250% at 500 mg/kg/day), cholangiolitis, diffuse liver cell degeneration and hypertrophy, necrosis, fibrosis, decreased serum glucose, increased levels of alkaline phosphatase, aspartate aminotransferase, alanine amino transferase, bilirubin, and triglycerides. The thymus was found to be small and upon microscopic examination to be atrophic or hypoplastic. Erythroid hypoplasia was found in the bone marrow of some of the rats dosed at 30 mg/kg/day and increased in severity with increasing dose. The erythroid hypoplasia was accompanied by a dose-related anemia. Even in the rats dosed at 8 mg/kg/day, very slight abnormalities in the bile ducts were observed upon microscopic examination of the liver. Chromatographic separation and analyses demonstrated that CSO contains about 58% 3- to 5-ring polycyclic aromatic hydrocarbons (PAHs) and approximately 8-10% carbazole derivatives. In vitro and in vivo skin penetration studies demonstrated that the carbazole materials penetrate through the skin to a considerable extent (about 44%); less penetration was observed with 2- or 3-ring (8-13%) or 5-ring PAHs (3%).
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PMID:Systemic toxicity from subchronic dermal exposure, chemical characterization, and dermal penetration of catalytically cracked clarified slurry oil. 359 Jan 98

Arotinoids, which are analogs of retinoic acid (RA) and retinol (RO) with the carbon skeleton in a rigid conformation, have more favorable therapeutic indices relative to all-trans-RA and all-trans-RO. The purpose of this investigation was to obtain preliminary in vivo toxicity data on SMR-2(analog of RO) and SMR-6 (analog of RA), arotinoids with promising activity (ED50's of 20 X 10(-11) and 5 X 10(-11) M, respectively; ED50 of RA = 1 X 10(-11) M) for reversal of keratinization in tracheal organ culture. A preliminary toxicity study was conducted in male B6D2F1 mice with gavage of retinoids in corn oil (0.01, 0.05, and 0.1 mg/kg/day of SMR-2 or SMR-6; 1, 5, and 10 mg/kg/day of RA as reference control). Due to lack of toxicity, each dose level for SMR-2 and SMR-6 was increased by 4-fold on Day 29 of dosing. The study was terminated on Day 57. Hypervitaminosis A (weight loss, alopecia, skin scaling, and bone thinning) was induced in the mid- and high-dose SMR groups; weight-gain depression was predominant in the high-dose RA group. The SMR compounds were approximately 100-fold more toxic, based on weight loss, than RA. In the SMR dose groups with hypervitaminosis A, white blood cell counts were elevated 2- to 4-fold; and there were microscopic lesions in skin, testes, epididymis, bone, thymus, bone marrow, peripheral lymph nodes, spleen, stomach, adrenal, and pituitary. The leukocytosis was attributed to leukopoiesis in spleen and bone marrow, which may be due to either a direct effect and/or a secondary response to a subacute inflammatory reaction in skin. Only peripheral lymph node hyperplasia was observed in SMR-2 and RA low-dose groups. Enlarged thymus, lymph node hyperplasia, leukopoiesis in spleen and bone marrow, elevated alkaline phosphatase with bone hypertrophy, and testicular degeneration were observed in the mid-dose RA group. The results indicate that immune stimulation may be a primary early response to retinoids and that skin, leukopoietic tissues, reproductive organs, stomach, and bone are primary targets for retinoid toxicity.
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PMID:Preliminary toxicity profile of arotinoids SMR-2 and SMR-6 in male B6D2F1 mice. 360 38

F344/N rats and B6C3F1 mice were exposed to 0, 1, 3, or 6 ppm methyl isocyanate by inhalation for 6 hr on 4 consecutive days. Deaths of rats were observed following 3 ppm exposures, and mice died after exposures to 6 ppm. Deaths appeared to be related to severe respiratory distress. Survivors in high dose groups lost weight initially, then gained weight at rates equal to controls throughout a 91-day recovery period. Lung weights increased significantly in male and female rats exposed to 3 ppm, but no persistent changes in brain, kidney, thymus, spleen, liver, or testis weights were seen in either mice or rats. Blood and serum from male and female rats were taken for clinical pathology and hematology assessments on day 7 of postexposure, the day prior to the first observed deaths of these animals. No changes or only slight changes were seen in measures of serum alanine aminotransferase, sorbitol dehydrogenase, alkaline phosphatase, or in blood and brain cholinesterase activities. However, serum creatine kinase increased with dose in both males and females. Blood urea nitrogen, creatinine, and methemoglobin were unchanged. No changes were seen in counts of red blood cells or platelets, or in red cell indices. Hemoglobin concentrations and hematocrits were slightly elevated. No changes were noted in absolute leukocyte counts, but counts of segmented neutrophils increased and lymphocytes decreased.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The toxicity of inhaled methyl isocyanate in F344/N rats and B6C3F1 mice. II. Repeated exposure and recovery studies. 362 27

Mammalian cells contain two subspecies of RNA polymerase II, designated IIO and IIA. The objectives of these studies were to determine the structural relationship between these subspecies and to determine the functional significance of these differences. Subunits IIo and IIa were purified from calf thymus, and the effect of alkaline phosphatase treatment on electrophoretic mobility and immunochemical reactivity was examined. The removal of phosphate converts subunit IIo to a form indistinguishable from that of subunit IIa. These results indicate that subunit IIo is produced by multisite phosphorylation of subunit IIa. The distribution of phosphate within subunit IIo was determined by CNBr cleavage of in vivo labeled HeLa cell RNA polymerase II. 32P-Labeled subunit IIo was purified by immunoprecipitation and cleaved with CNBr, and the resultant peptides were analyzed. The quantitative recovery of 32P in the C-terminal peptide establishes that this domain is the primary site of phosphorylation. In an effort to assess the level of phosphorylation of the transcriptionally active form of RNA polymerase II in HeLa nuclei, transcription was carried out in the presence of 4-thiouracil triphosphate and the nascent labeled transcript cross-linked to RNA polymerase. Specific photoaffinity labeling of subunit IIo was observed. Alkaline phosphatase treatment results in an increase in the mobility of photoaffinity labeled subunit IIo to approach that of subunit IIa. These results indicate that subunit IIo is a component of transcriptionally active RNA polymerase II.
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PMID:Messenger RNA synthesis in mammalian cells is catalyzed by the phosphorylated form of RNA polymerase II. 362 68


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