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:3.4.24.3 (collagenase)
18,340 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have studied the effect of colchicine and related compounds on secretion of enzymes by thioglycollated-elicited mouse peritoneal macrophages in culture. Colchicine stimulated secretion of inducible neutral proteinase activities of elastase (EC 3.4.21.11), collagenase (EC 3.4.24.3), gelatinase (pepsin B; EC 3.4.23.2), and azocaseinase 2- to 6-fold for a period of several days, but inhibited the production and release of lysozyme (mucopeptide N-acetylmuramoylhydrolase; EC 3.2.1.17), a noninducible macrophage secretory product. Parallel changes were observed in cell morphology and secretion after treatment with colchicine, Colcemid, and vinblastine, but not with lumicolchicine, and these effects could be gradually reversed by withdrawal of colchicine. Cytochalasin B also stimulated secretion of elastase 2- to 3-fold but did not influence release of lysozyme. These results demonstrate that tubulin-binding drugs may have opposite effects in macrophages than those usually reported for other experimental systems and also provide evidence for the nonparallel discharge of different macrophage secretion products.
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PMID:Secretion of macrophage neutral proteinase is enhanced by colchicine. 17 59

Leucine-binding protein described in an earlier paper was examined to characterize the dynamic properties of the system. Leucine-binding protein assembles into a large protein polymer or complex (greater than 302,000 daltons). Colchicine reduces and Mg2+ increases the amount of polymer formed. Trypsin destroys the isolated polymer but RNAase and collagenase do not. Mg2+-ATPase activity is present in the polymer fraction. The formation of the large complex suggests a quickly adaptable structure capable of responding to ionic and environmental conditions.
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PMID:Aggregation of binding protein from rat nerve. 72 98

Colchicine, which has been used for hundreds of years in the treatment of gout, has found a new use in the treatment of cirrhosis. In the experimental animal, and in vitro, colchicine decreases inflammation, inhibits collagen synthesis and also increases collagen degradation by activating collagenase. Many of the putative beneficial actions of the drug in cirrhosis, as well as its toxic side effects, are due to the fact that it binds to tubulin and thereby disrupts microtubules; however, it is unclear which of these actions, mostly demonstrated in the experimental animal, are present in the doses currently used in man. There have been 4 controlled trials of colchicine in various forms of cirrhosis, three of which have concerned primary biliary cirrhosis. Data are currently available on 146 colchicine-treated patients, of which 92 had primary biliary cirrhosis. Colchicine improves the conventional liver function tests in primary biliary cirrhosis and also reverses the basic defect in hepatic excretory capacity characteristic of this disease. The drug appears to have no significant effect on symptoms, clinical features or liver histology, but in 2 of the 3 primary biliary cirrhosis trials, as in the Mexican study of alcoholic and post-hepatitic cirrhosis, colchicine treatment was associated with improved survival.
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PMID:Colchicine in primary biliary cirrhosis. 177 43

Colchicine induced a rapid destruction of the collagenous matrix of pig synovial explants in culture in the presence of serum. The most efficacious doses were 0.01-0.1 micrograms/ml (2.5 x 10(-8) M - 2.5 x 10(-7) M). The histological progression of the tissue breakdown induced by colchicine was very similar, although faster, to that described for other agents (Fell et al., 1986), with cells having basophilic nuclei accumulating in areas of fibril degradation. The loss of collagen correlated with an increase in collagenase production and at the peak of resorption (6 to 8 days) active collagenase was present in the culture media. Immunocytochemical methods demonstrated active collagenase bound to collagen fibrils after only 4 days in culture, before significant collagen degradation could be observed histologically. Collagen breakdown was completely inhibited by cortisol, and partially inhibited by indomethacin: only the inhibition by indomethacin could be reversed by exogenous prostaglandin E2. Vinblastine at a higher dose was as effective as colchicine but the lumicolchicines, which do not disrupt microtubules, were ineffective. Although the precise mechanism of action of colchicine is unknown, this culture system provides a useful in vitro model for increasing our understanding of the cellular mechanisms of tissue breakdown and for elucidating the roles of active collagenase and related metalloproteinases.
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PMID:The degradation of collagen in pig synovium in vitro and the effect of colchicine. 254 41

In July 1986, a 46-year old male patient was admitted for a bullous skin disease of 4 years' duration. The disease fulfilled all the criteria of epidermolysis bullosa acquisita (EBA), as laid down by Roenigk and Pearson. Despite a guided investigation, none of the diseases classically associated with EBA could be found, but it must be noted that immunological stigmata of an old hepatitis B were present. After failures or partial results with prednisone alone (1 mg/kg/day from August to October 1986), then methotrexate (30 mg/week) combined with prednisone (20 mg/day), the patient was treated with colchicine in doses of 2 mg per day, and within a fortnight a dramatic improvement of buccal mucosal lesions and cutaneous fragility was observed. Colchicine was withdrawn, but 5 days later bullae and erosions of the mucosa reappeared. The reintroduction of colchicine in the same doses (2 mg/day) resulted in remission of the lesions. The disease has now remained stable for one year under colchicine 1 mg/day. Four attempts at reducing this dosage to 1 mg every other day brought about the recurrence of a few bullae and of cutaneous fragility. To our knowledge, colchicine has not yet been reported to be effective in the treatment of EBA. Its effectiveness may be due, to a great extent, to its immunomodulating properties, notably on some functions of neutrophils the role of which in the pathogenesis of bullous lesions seems to have been established. By modulating collagen synthesis and collagenase activity colchicine might induce structural modifications of the EBA antigen, identified as the carboxyterminal group of type VII collagen, and inhibit its recognition by autoantibodies.
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PMID:[Value of colchicine in treating acquired epidermolysis bullosa]. 267 32

Activation of macrophages results in the production of tissue destructive mediators and enzymes including prostaglandins (PGE) and collagenase. In addition, activated macrophages also generate mediators which enhance connective tissue formation through their effects on fibroblast growth. To determine whether the pro-inflammatory mediators and the mediator(s) involved in tissue repair are under the same regulatory control, guinea pig macrophage cultures were treated with various pharmacologic agents and their supernatants monitored for biologic activity. The nonsteroidal anti-inflammatory agent, indomethacin, and the glucocorticoid, dexamethasone, at pharmacologic concentrations inhibited not only prostaglandin synthesis (greater than 90%) but also the production of collagenase (greater than 90%). Colchicine, a microtubule disruptive agent, but not the inactive form, lumicolchicine, markedly diminished the production of collagenase independently of prostaglandin synthesis. In contrast to the inhibitory effects of these anti-inflammatory agents on PGE and collagenase production, indomethacin did not inhibit the production of macrophage-derived fibroblast-activating factor (FAF). Furthermore, dexamethasone at pharmacologic doses did not inhibit FAF production. Colchicine not only did not inhibit FAF, but frequently enhanced the appearance of FAF In the macrophage cultures. Thus, it appears that regulation of the production of PGE and collagenase is different than the regulation of FAF synthesis and therefore the production of these mediators can be differentially modulated. Such a dissociation may provide a basis for mononuclear cell-mediated fibroblast growth and tissue repair to occur independently of the release of PGE2 and collagenase and even following anti-inflammatory drug therapy.
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PMID:Regulation of macrophage collagenase, prostaglandin, and fibroblast-activating-factor production by anti-inflammatory agents: different regulatory mechanisms for tissue injury and repair. 298 53

Cathepsins B and D, beta-galactosidase, and acid phosphatase activities were found to be decreased in the regenerating rat liver, the reduction being maximal around the peak of hepatocyte mitoses (30 h). To investigate whether these changes could be heterogeneously distributed among hepatic cells, total cell populations from control or two-thirds hepatectomized rat livers were dissociated by the collagenase perfusion technique and analysed by different procedures. Isopycnic centrifugation in a Metrizamide gradient satisfactorily resolved hepatocytes and non-parenchymal cells from control animals but was not adequate when applied to 30-h regenerating liver cells. Colchicine treatment of the hepatectomized animals, resulted in substantial accumulation of phase M-hepatocytes. Subpopulations considerably enriched in fast-sedimenting phase M-cells were obtained by sedimentation at 1 g of the total liver cell population, and subsequently analysed by isopycnic equilibration. Phase M-hepatocytes were shown to have markedly reduced levels of beta-galactosidase, acid phosphatase, and cathepsin B activities in comparison, not only with control hepatocytes, but also with those parenchymal cells which were not metaphase-arrested in the same regenerating livers. Therefore, in partially-hepatectomized rats, hepatocytes progressing up to metaphase in the first mitotic cycle exhibited a selective depletion of lysosomal enzyme activities. The mechanism(s) underlying this change remain(s) presently unknown.
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PMID:Cellular distribution of lysosomal hydrolase activities in the regenerating rat liver. 308 41

Colchicine, an antimicrotubular agent, was shown to block the transcellular movement of certain structural macromolecules such as collagen. In the present study, the effect of colchicine on collagen synthesis and secretion by monolayer cultures of fibroblasts from livers of mice infected with Schistosoma mansoni was investigated. The effect of colchicine on proliferation of these fibroblasts was studied as well. Collagen and non-collagen protein synthesis was measured by incubating cultures with [14C]proline and measuring the incorporation of radioactivity into these protein fractions in both culture media and cell layers. Proliferation was measured by [3H]thymidine uptake. The isolated fibroblasts actively formed collagen and secreted most of it into the culture medium; 10-20% of the collagenase-sensitive radioactive protein remained in the cell layer. The addition of colchicine to culture medium led to selective inhibition of collagen formation with negligible effects on non-collagen protein synthesis. Fibroblast proliferation was also reduced by colchicine treatment. Both inhibition of collagen synthesis and inhibition of fibroblast proliferation were dose-dependent. Comparison of medium and cell layer collagen radioactivity confirmed inhibition of synthesis rather than only inhibition of secretion. These data suggest that colchicine has a specific effect on synthesis of collagen and proliferative activity by fibroblasts from S. mansoni-infected liver and may, therefore, be useful in modulating schistosomal hepatic fibrosis.
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PMID:Effect of colchicine on collagen synthesis by liver fibroblasts in murine schistosomiasis. 314 Oct 89

This study investigated the importance of reorganization of cell components by cytoskeletal structures to the short-term dynamic changes in LH release from dispersed sheep pituitary cells in perifusion, when stimulated with different dynamic patterns of gonadotrophin-releasing hormone (GnRH). The changes in rate of LH release investigated were the initial response to GnRH, desensitization, change of dose-response during desensitization, and recovery of sensitivity between pulses of stimulation. Cytochalasin D and colchicine were used to modify microfilament and microtubule action respectively. To determine whether receptor movement after binding of agonist was involved in the altered responses, K+ and phorbol 12-myristate 13-acetate (PMA) were used as stimulants because they cause LH release independently of agonist-receptor interaction. After 3 and 48 h culture on dextran beads and 2-3 h incubation in the presence and absence of 2-48 mumol cytochalasin D/1, or 8 or 250 mumol colchicine/l, aliquots of collagenase-dispersed sheep pituitary cells were stimulated at 37 degrees C in tubes or in a multicolumn perifusion system with 850 pmol GnRH/1, 109 mmol K+/1 or 10 nmol PMA/1. Fractions of supernatant or effluent were collected at intervals and LH concentrations measured by radioimmunoassay. Control samples were treated in the same way but without stimulation. Maximal, reversible enhancement of LH release over the first 20 min following stimulation with all secretagogues was observed after incubation of cells in 6 mumol cytochalasin/l. Desensitization behaviour, the supramaximal response, and the ability of cells to recover sensitivity to repeated pulses of GnRH were not altered by this modifier of microfilament polymerization at 6 or 24 mumol/ml. Colchicine at 8 mumol/l caused no changes in LH release. At 250 mumol/l, colchicine reduced the initial response of cells to GnRH stimulation but its action at this relatively high level may not be specific; there was no other major change in desensitization patterns, nor recovery of sensitivity to pulsed GnRH stimulation. Each treatment affected cellular responses similarly before and after culture. From studying the details of the dynamics of the short-term responses of gonadotrophs, we conclude that transport of cell components involving microfilaments and microtubules is unlikely to be a major limitation on the rate of LH release during desensitization, the supramaximal response, or the recovery of sensitivity between pulses of GnRH. This suggests that biochemical reactions rather than physical translocation may be rate-limiting in these processes.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Effects of modifiers of cytoskeletal structures on the dynamics of release of LH from sheep anterior pituitary cells stimulated with gonadotrophin-releasing hormone, K+ or phorbol ester. 354 73

Colchicine has been reported to disrupt microtubules and thereby inhibit collagen secretion. Because of this "anti-collagen" activity, colchicine has been suggested for use in the treatment of hepatic fibrosis. Using biochemical and immunohistochemical techniques, our laboratory has identified the hepatocyte as one possible source of collagen in the liver. The present study examined the direct effect of colchicine on collagen secretion by hepatocytes in culture. Parenchymal cells were isolated from the livers of adult rats four days following a two-thirds hepatectomy. Total collagen and the fraction secreted into the medium were quantitated as incorporation of [3H]-proline into bacterial collagenase-sensitive protein. Treatment of the hepatocytes with 100 microM colchicine (2-3 hours) resulted in a substantial inhibition of collagen secretion. However, upon longer exposure of the hepatocytes to the drug (24 hours and 8 days), the inhibitory effect on collagen secretion was abolished. The anti-protein secretion activity of the colchicine in the conditioned medium removed from the hepatocytes was still present as verified by a 2.5 hour fibroblast-collagen secretion bioassay. The secretion of the plasma proteins albumin, fibrinogen and the third component of complement was not altered by the presence of colchicine. We conclude that the hepatocyte is a highly efficient secretory cell, and is not entirely dependent upon microtubules as organelles for protein secretion. Therefore, to the extent that hepatocytes may contribute to the hepatic fibrosis, the therapeutic use of colchicine to block collagen secretion might be expected to have only limited effectiveness.
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PMID:Colchicine does not provide a sustained blockage of collagen and plasma protein secretion by rat hepatocytes. 358 54


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