Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.3.1 (alkaline phosphatase)
 47,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Estrogen replacement therapy has been correlated with an increased risk for developing breast and endometrial cancers. One potential mechanism of estrogen carcinogenesis involves metabolism of estrogens to 2- and 4-hydroxylated catechols, which are further oxidized to electrophilic/redox active o-quinones that have the potential to both initiate and promote the carcinogenic process. Previously, we showed that the equine estrogens, equilin and equilenin, which are major components of the estrogen replacement formulation Premarin (Wyeth-Ayerst), are primarily metabolized to the catechol, 4-hydroxyequilenin. This catechol was found to autoxidize to an o-quinone causing oxidation and alkylation of DNA in vitro and in vivo. To block catechol formation from equilenin, 4-halogenated equilenin derivatives were synthesized. These derivatives were tested for their ability to bind to the estrogen receptor, induce estrogen sensitive genes, and their potential to form catechol metabolites. We found that the 4-fluoro derivatives were more estrogenic than the 4-chloro and 4-bromo derivatives as demonstrated by a higher binding affinity for estrogen receptors alpha and beta, an enhanced induction of alkaline phosphatase activity in Ishikawa cells, pS2 expression in S30 cells, and PR expression in Ishikawa cells. Incubation of these compounds with tyrosinase in the presence of GSH showed that the halogenated equilenin compounds formed less catechol GSH conjugates than the parent compounds, equilenin and 17beta-hydroxyequilenin. In addition, these halogenated compounds showed less cytotoxicity in the presence of tyrosinase than the parent compounds in S30 cells. Also, as stated above, the 4-fluoro derivatives showed similar estrogenic effects as compared with parent compounds; however, they were less toxic in S30 cells as compared to equilenin and 17beta-equilenin. Because 17beta-hydroxy-4-halogenated equilenin derivatives showed higher estrogenic effects than the halogenated equilenin derivatives in vitro, we studied the relative ability of the 17beta-hydroxy-4-halogenated equilenin derivatives to induce estrogenic effects in the ovariectomized rat model. The 4-fluoro derivative showed higher activity than 4-chloro and 4-bromo derivatives as demonstrated by inducing higher vaginal cellular differentiation, uterine growth, and mammary gland branching. However, 17beta-hydroxy-4-fluoroequilenin showed a lower estrogenic activity than 17beta-hydroxyequilenin and estradiol, which could be due to alternative pharmacokinetic properties for these compounds. These data suggest that the 4-fluoroequilenin derivatives have promise as alternatives to traditional estrogen replacement therapy due to their similar estrogenic properties with less overall toxicity.
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PMID:Effect of halogenated substituents on the metabolism and estrogenic effects of the equine estrogen, equilenin. 1280 57

Hypochlorous acid (HOCl), generated from H2O2 and Cl- by myeloperoxidase in activated neutrophils, causes tissue damage during inflammation. We have developed a simple, sensitive (approximately 0.2 fmol on column) and specific GC-MS assay for the detection of 5-chlorouracil (5-ClUra), a signature product of HOCl-mediated damage to nucleobases. In this assay, 5-ClUra is released from isolated DNA by a digestion with nuclease P1, alkaline phosphatase, and thymidine phosphorylase (TP), or from chlorinated nucleosides in biological fluids by TP. The freed 5-ClUra is derivatized with 3, 5-bis-(trifluoromethyl)-benzyl bromide, which is detected by negative chemical ionization mass spectrometry. The assay can be used to simultaneously detect other halogenated uracils including bromouracil. Using this assay, we showed that 5-ClUra is generated by the reaction of low micromolar HOCl with (deoxy)cytidine, (deoxy)uridine, and DNA. In cell cultures, an increase of 5-ClUra was detected in DNA when cells were treated with sublethal doses of HOCl and allowed to proliferate. The elevation of 5-ClUra was markedly accentuated when physiologically relevant concentrations of (deoxy)uridine, (deoxy) cytidine, uracil, or cytosine were present in the medium during HOCl treatment. In the carrageenan-induced inflammation model in rats, chlorinated nucleosides was significantly increased, compared with controls, in the exudate fluid isolated from the inflammation site. Our study provides the direct evidence that chlorinated nucleosides are found in the inflammation site and can be incorporated in DNA during cell/tissue proliferation. These findings may be relevant to the carcinogenesis associated with chronic inflammation.
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PMID:5-Chlorouracil, a marker of DNA damage from hypochlorous acid during inflammation. A gas chromatography-mass spectrometry assay. 1281 Jul 14

Plant-derived phenolic compounds manifest many beneficial effects and can potentially inhibit several stages of carcinogenesis. In the present study, we investigated the efficacy of Emblica officinalis (E. officinalis) polyphenol fraction (EOP) on the induction of apoptosis in mouse and human carcinoma cell lineses and its modulatory effect on N- nitrosodiethylamine (NDEA) induced liver tumors in rats. The results indicate that EOP treatment could induce apoptosis in Dalton's Lymphoma Ascites (DLA) and CeHa cell lines At 200 microg/ml dose EOP induced membrane blebbing, chromatin condensation and intenucleosomal breaks as evident from the morphology and DNA ladder pattern obtained in gel electrophoresis. The results also suggested that EOP treatment could decrease the liver tumour development induced by NDEA. Animals administered (oral) with NDEA (0.02%, 2.5 ml/rat, 5 days a week, 20 weeks) developed visible liver tumours by the end of the 20th week and the liver weight raised to 5.2 +/- 1.1 g/ 100 g body weight. Only 11% of the animals treated with EOP (60 mg/kg, oral, 5 days a week for 20 weeks) developed visible liver tumours by this period and the liver weights were reduced to 3.2 +/- 0.7 g/ 100 g body weight. gamma-glutamyl transpeptidase activity was raised to 88.4 +/- 16.2 U/l in serum of NDEA treated group was reduced to 48.4 +/- 14.8 U/l by EOP treatment. Elevated levels of serum alkaline phosphatase (ALP), glutamate pyruvate transaminase (GPT), bilirubin, liver glutathione S-transferase (GST) and glutathione (GSH) in the NDEA administered group were significantly reduced by EOP treatment. The EOP was found to scavenge superoxide and hydroxyl radicals and inhibit lipid peroxidation in vitro. EOP also inhibited DNA topoisomerase I in Saccharomyces cervisiae mutant cell cultures and the activity of cdc25 tyrosine phosphatase.
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PMID:Induction of apoptosis in mouse and human carcinoma cell lines by Emblica officinalis polyphenols and its effect on chemical carcinogenesis. 1286 70

Impediment of the promotion and progression stages of carcinogenesis of the prostate could have a profound impact on treatment choice and prognosis for prostate cancer. Efficacious chemopreventive agents that elicit their activity by slowing the processes of progression could make watchful waiting a viable alternative for a large population of men or could delay the necessity for surgery, radiation or other more invasive treatment modalities associated with frequent side effects. Reports from the Nutritional Prevention of Cancer (NPC) study reported that dietary supplementation with selenium significantly reduced the risk of developing prostate cancer. These data led to initiation of the Watchful Waiting Study, a phase II, multi-center, randomized, double-blind, placebo-controlled clinical intervention study testing the effects of two doses of selenized yeast on progression of prostate cancer. Participants are men with biopsy-proven prostate cancer who have elected to forgo therapy and be closely followed by 'watchful waiting' that includes quarterly prostate-specific antigen (PSA) screening. Subjects are randomized to receive 200 or 800 microg of selenized yeast or matched placebo daily. Endpoints include time to disease progression and PSA velocity. Secondary endpoints include time to initiation of therapy as well as biochemical markers of disease progression including chromagranin A and alkaline phosphatase. Immunohistochemical analyses for indicators of apoptosis, proliferation and differentiation will be performed on baseline and subsequent prostate biopsy specimens. This report summarizes the primary objectives, research methods and the randomized subjects in this important clinical trial.
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PMID:Selenium and inhibition of disease progression in men diagnosed with prostate carcinoma: study design and baseline characteristics of the 'Watchful Waiting' Study. 1450 81

A single dose of 10 mg of 7,12-dimethylbenz[a]anthracene (DMBA), administered to rats through intragastric intubation, was sufficient to induce many biochemical and histopathological changes in their mammary tissue. Significant increases were observed in the activity levels of the enzymes acid ribonuclease, 5-nucleotidase, alkaline phosphatase, and beta-glucuronidase in mammary tissue homogenates of DMBA-treated rats after an experimental period of five months. Histopathological studies of the mammary tissue also revealed malignant epithelial tumors (cribriform carcinoma) induced among 85% of the treated rats, with an incidence of 4 tumors in 12 mammary glands. Nevertheless, administration of 30% soybean in the diet of rats or 5,000 ppm ascorbic acid in their drinking water in addition to DMBA revealed a significant chemoprotective effect against the carcinogenesis induced by DMBA alone. This chemoprotective effect was demonstrated by the normalization of the activity levels of the enzymes studied in mammary tissue homogenates, because most of the enzymes were maintained at near the levels in the control animals. The incidence and number of tumors were also decreased. Cribriform carcinoma was observed in 50% of the rats, and the incidence of the affected glands was 2 in 12 mammary glands among both groups. On the other hand, a less chemoprotective effect was observed due to Vicia faba administration.
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PMID:Effect of soybean, Vicia faba, and vitamin C on the carcinogenicity of DMBA. 1450 48

Sphingomyelin (SM) metabolism in the gut has been implicated in colonic tumorigenesis. Intestinal alkaline sphingomyelinase (alk-SMase) hydrolyses SM in the intestinal content and at the brush border. The enzyme activity is decreased in the tissues of human colorectal tumours. This study examines whether site or chain-mutation of alk-SMase occurs in colon cancer HT-29 cells and Caco-2 cells. Total RNA was isolated and the cDNA of alk-SMase was amplified by RT-PCR. The size of the cDNA from HT-29 cells was smaller than that of the wild-type cDNA. DNA sequencing identified a deletion of exon 4 in alk-SMase cDNA in HT-29 cells. No mutation in genomic alk-SMase DNA from exon 3 to 5 was identified. The exon 4 deletion was caused by a shift of RNA splice site in chromosome 17q25. In Caco-2 cells, no mutation of alk-SMase cDNA was identified. Transient expression in COS-7 cells showed that the enzyme from the cDNA in HT-29 cells had little alk-SMase activity whereas that in Caco-2 cells was as active as the wild-type alk-SMase. The deleted region included residue His353, which is predicted to form a substrate-binding site of alk-SMase. H353A substitution resulted in a protein with no alk-SMase activity. In monolayer cultured Caco-2 cells and HT-29 cells the alk-SMase activities were low. However, to culture the cells under polarizing conditions increased alk-SMase activity and reduced SM level in Caco-2 cells. The alk-SMase activity varied in parallel with alkaline phosphatase activity. In conclusion, we identified an inactive deletion in alk-SMase in HT-29 cells, and a differentiation-related expression of the enzyme in Caco-2 cells. The results provide a molecular mechanism related to previous findings of reduced alk-SMase activity in human colon cancers.
Carcinogenesis 2004 Aug
PMID:Identification of one exon deletion of intestinal alkaline sphingomyelinase in colon cancer HT-29 cells and a differentiation-related expression of the wild-type enzyme in Caco-2 cells. 1501 55

The chronic toxic effects of a prolonged exposure of 6 months, from January to June, to a 'safe dose' (0.20 mg litre(-1)) of a commercial organomercurial fungicide, Emisan (methoxy ethyl mercuric chloride: MeEHgCl), on the histophysiology of liver in adults and young (yearlings) of Channa punctatus, are described in this investigation. In both of the experimental groups, liver histology exhibited various abnormalities, including hyperplasia, nuclear pyknosis, fatty necrosis, and degeneration of hepatocytes leading to tumour and syncytium formation, which are indicative of carcinogenesis. Apart from this, blood vessel congestion and oedema were also observed in young treated fish. In the livers of both exposed groups, corresponding with this cellular damage, a marked reduction in hepatosomatic index, levels of total protein and lipid, and an elevation in cholesterol and acid and alkaline phosphatase contents were recorded. However, these alterations were more pronounced in young than in adult fish. These Emisan-induced, histopathological and biochemical changes are suggestive of severe hepatic dysfunction, which may result in the impairment of the physio-metabolic process, in this species.
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PMID:Histopathological and biochemical changes in the liver of a teleost fish, Channa punctatus (Bloch) induced by a mercurial fungicide. 1509 15

The anticancer efficacy of tocotrienol-rich fraction (TRF) was evaluated during diethylnitrosamine (DEN)/2-acetylaminofluorene (AAF)-induced hepatocarcinogenesis in male Sprague-Dawley rats. TRF treatment was carried out for 6 months, and was started 2 weeks before initiation phase of hepatocarcinogenesis. Morphological examination of the livers from DEN/AAF rats showed numerous off-white patches and few small nodules, which were significantly reduced by TRF treatment. Cytotoxic damage by DEN/AAF was estimated by alkaline phosphatase (ALP) release into the plasma from the cell membranes. DEN/AAF caused a twofold increase in the activity of ALP in plasma as compared with normal control rats, and this increase was prevented significantly by TRF treatment. We observed an increase of 79% in liver ALP activity in DEN/AAF rats, which was further increased by another 48% after the administration of TRF. Hepatic activity of glutathione S-transferase (GST) was also increased (3.5-fold) during the induction of hepatic carcinogenesis. Lipid peroxidation and low-density lipoprotein (LDL) oxidation increased threefold following initiation by DEN/AAF as compared with normal control rats. However, TRF treatment to DEN/AAF-treated rats substantially decreased (62-66%) the above parameters and thus limited the action of DEN/AAF. We conclude that long-term intake of TRF could reduce cancer risk by preventing hepatic lipid peroxidation and protein oxidation damage due to its antioxidant actions.
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PMID:Suppression of diethylnitrosamine and 2-acetylaminofluorene-induced hepatocarcinogenesis in rats by tocotrienol-rich fraction isolated from rice bran oil. 1554 46

Kaempferol induces differentiation in partially differentiated colon cancer cells which express low levels of connexin43 protein and connexin43 mRNA (KNC cells). Differentiation was observed as changes in cell morphology and the activity of alkaline phosphatase. Increased differentiation in kaempferol-treated KNC cells correlated with restoration of gap junctional intercellular communication (GJIC), increased levels of connexin43 protein and its phosphorylation status. Phosphorylation (activation) of Stat3 and Erk was also reduced by kaempferol. An inhibitor of Stat3 phosphorylation also induced morphological changes in KNC cells similar to those in kaempferol-treated cells, suggesting that kaempferol-induced differentiation may be mediated by inhibition of Stat3 phosphorylation. These effects were not observed in HCT116 cells, a poorly differentiated colon cancer cell line deficient in expression of connexin43 mRNA and connexin43 protein. In conclusion, kaempferol might function as an anticancer agent by re-establishing GJIC through enhancement of the expression and phosphorylation of connexin43 protein in a tumorigenic colon cancer cell line that already expresses connexin43 mRNA via a Stat3-dependent mechanism. In contrast, kaempferol had no effect in a tumorigenic colon cancer cell line that did not express connexin43 mRNA and was deficient in GJIC.
Carcinogenesis 2005 Mar
PMID:Augmentation of differentiation and gap junction function by kaempferol in partially differentiated colon cancer cells. 1561 37

The mycotoxin alternariol (AOH) is found in food and beverages infected by Alternaria alternata. Because consumption of foodstuffs contaminated with A. alternata has been implicated in an elevated incidence of esophageal carcinogenesis, we have investigated the estrogenic potential, the effect on cell proliferation, and the genotoxic effect of AOH in cultured mammalian cells. AOH replaced E2 from isolated human estrogen receptors alpha and beta and increased the level of alkaline phosphatase (ALP) mRNA and the enzymatic activity of ALP in a human endometrial adenocarcinoma cell line (Ishikawa cells). The estrogenicity of AOH was about 0.01% of that of E2. The effects in Ishikawa cells were reversed by the ER antagonist ICI 182,780. Analysis of cell proliferation by flow cytometry and microscopy of Ishikawa and Chinese hamster V79 cells revealed that AOH inhibited cell proliferation by interference with the cell cycle. The genotoxic potential was assessed by the micronucleus (MN) assay and immunochemical differentiation between MN containing whole chromosomes (kinetochore-positive) and DNA fragments (kinetochore-negative) in Ishikawa and V79 cells. AOH induced kinetochore-negative MN in both cell lines. This is the first report on the estrogenic potential, inhibition of cell proliferation and clastogenicity of AOH in Ishikawa and V79 cells in vitro.
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PMID:Estrogenic and clastogenic potential of the mycotoxin alternariol in cultured mammalian cells. 1619 92


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