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PubMed2003

Colchicine down-regulates cytochrome P450 2B6, 2C8, 2C9, and 3A4 in human hepatocytes by affecting their glucocorticoid receptor-mediated regulation.

The xenobiotic-mediated induction of three major human liver cytochrome P450 genes, CYP2B6, CYP2C9, and CYP3A4, is known to be regulated by the constitutive androstane receptor (CAR) and the pregnane X receptor (PXR). CAR and PXR are regulated, at least in part, by the glucocorticoid receptor (GR) and the hypothesis of a signal transduction cascade GR-[CAR/PXR]-P450 has been proposed. This study was aimed at testing this hypothesis in primary human hepatocytes by using the tubulin network disrupting agent colchicine. Colchicine (COL) decreased both basal and rifampicin- and phenobarbital-inducible expression of CYP2B6, CYP2C8/9, and CYP3A4. A parallel down-regulation of mRNA expression of CAR, PXR, and tyrosine aminotransferase, a prototypic gene directly regulated by GR, was observed. COL affected neither the level of GR mRNA nor ligand binding to GR. To evaluate the effect of colchicine on GR-mediated gene transactivation, HeLa cells stably or transiently transfected with a GR-responsive element-dependent luciferase reporter gene were used. COL decreased the dexamethasone-induced luciferase expression in stably transfected cell line by 50%, whereas GR transactivation in transiently transfected cells was not affected by COL. In contrast, ligand-dependent GR translocation in the human embryonic kidney 293 cell line transiently transfected with GFP-GR was inhibited by COL. We conclude that alteration of the signal transduction mediated through the GR-[CAR/PXR]-P450 cascade by colchicine is responsible for the down-regulation of CYP2C9 and CYP3A4, implicating cytoskeleton as necessary for correct functioning of this cascade under physiological conditions.

Animals↗
PubMed1969

Colchicine-inhibited cilia regeneration: explanation for lack of effect in tris buffer medium.

In Stentor coeruleus growth of new, daughter ciliates and experimentaly inducled regeneration of oral membranellar cilia are reversibly inhibited by low, nontoxic concentrations of colchicine. However, if the clulture medium containing colchicine (or Colcemid) is made up in tris(hydroxymethyl)aminomethane buffer, growth of ciliated daughters and regeneration of oral cilia proceed normally. The evidence suggests that the mechanism of this reversal of the effects of colchicine (or Colcemid) is due to a chemical reaction between tris(hydroxymethyl)-aminomethane (or its hydrochloride, or both) and colchicine (or Colcemid), wihich reduces the effective concentration of these mitotic spindle inhibitors reaching the stentors.

Animals↗
PubMed1992

Salicylates used in inflammatory bowel disease and colchicine impair interferon-gamma induced HLA-DR expression.

Colonic epithelial cells express HLA-DR in inflammatory bowel disease. The effect of drugs used in the treatment of inflammatory bowel disease and colchicine on interferon-gamma (IFN-gamma) induced DR expression has been investigated. HT-29 cells were cultured in 25 cm2 flasks. At 48 hours interferon-gamma (0, 50, or 100 U/ml) +/- drug were added. At 120 hours the cells were stained for HLA-DR and analysed by flow cytometry. 10(-2) M 5ASA reduced DR expression induced by 50 U/ml interferon-gamma from 62 (12)% of cells (mean SD) to 29 (20)% (p less than 0.005). Corresponding figures for 10(-2) M N-acetyl 5ASA were 68 (16)% to 39 (17)% (p less than 0.05); for 10(-2) M 4ASA, 61 (4)% to 57 (4)% (p = 0.6); for 10(-2) M N-acetyl 4ASA, 60 (12)% to 35 (13)% (p less than 0.05); for 10(-2) M olsalazine, 72 (9)% to 3 (1)% (p less than 0.001); for 10(-3) M olsalazine, 72 (9)% to 16 (10)% (p less than 0.001); for 10(-6) M colchicine, 62 (13)% to 5 (3)% (p less than 0.001); and for 10(-7) M colchicine, 62 (13)% to 10 (3)%. Similar results were obtained when DR was induced by 100 U/ml of interferon-gamma except with 10(-2) M 4ASA which reduced expression from 77 (4)% to 68 (3)% (p less than 0.05). Sulphapyridine, prednisolone, indomethacin and cyclosporin A had no effect. Concurrent staining with propidium iodide showed that these results were unchanged when viable cells alone were analysed. Prior incubation of cells with drug, followed by washing, had no effect on interferon-gamma induced DR expression. 5ASA, N-acetyl 5ASA, 4ASA, N-acetyl 4ASA, olsalazine and colchicine reduce interferon-gamma induced HLA-DR expression. In inflammatory bowel disease these compounds may impair antigen presentation by the colonic epithelium.

Aminosalicylic Acid↗
PubMed1993

Reversal of carbon tetrachloride induced changes in microviscosity and lipid composition of liver plasma membrane by colchicine in rats.

Colchicine is beneficial in the treatment of cirrhotic patients, it prevents changes in plasma membrane bound enzymes induced by CCl4 intoxication. In this study, lipid composition and microviscosity were measured in liver plasma membranes isolated from rats given CCl4. Microviscosity values increased in rats given CCl4 for six weeks but fell considerably in those given CCl4 for 10 weeks. Both these changes were absent when colchicine was given with CCl4. The cholesterol/phospholipid molar ratios and lipid peroxide values increased but plasma membrane phospholipids, the length of fatty acyl chains, and the unsaturation index fell significantly after CCl4 intoxication. Colchicine treatment also prevented these changes. Changes in the lipid composition of liver plasma membranes were significantly correlated with lipid peroxidation. Colchicine prevents changes in the physicochemical properties of liver plasma membranes induced by longterm CCl4 treatment, probably by blocking peroxidation of unsaturated fatty acids.

Animals↗
PubMed1987

Characterization of serum, liver, and intestinal sialyltransferases from rats treated with colchicine.

A modified high pressure liquid chromatographic method using lactose (Gal beta 1----4Glc) as an exogenous acceptor has been used to characterize the sialyltransferases known to increase in the serum of colchicine-treated rats. The results show a 10-fold increase of Gal beta 1----4GlcNAc alpha 2----6 sialyltransferase (alpha 2----6 ST), whereas the Gal beta 1----3GlcNAc alpha 2----3 sialyltransferase showed only 1.6-fold increase in the serum after 17 h of colchicine treatment. The sialyltransferase activity in serum using exogenous desialylated, alpha 1-acid glycoprotein as acceptor also showed an eightfold increase. In liver homogenate and Golgi membrane, the sialyltransferase activity when assayed with desialylated alpha 1-acid glycoprotein as acceptor showed a slight decrease after 4 h, but returned to normal level after 17 h. A similar trend was seen when the two transferases were assayed with lactose as acceptor. The antiserum to rat alpha 2----6 ST inhibited the sialyltransferase activity in serum, liver, and jejunal incubation medium. Jejunal sections from rats treated with colchicine for 4 h in presence of heated serum showed a decrease of sialyltransferase, with consequent increase of the alpha 2----6 ST enzyme activity in the medium. This result suggests that intestinal tissue could be a source of increased serum enzyme activity in colchicine treatment.

Animals↗
PubMed1988

Effect of colchicine on alkaline triglyceride lipase activity and triglyceride content in rat skeletal muscle.

One purpose of this study was to determine if colchicine increased intracellular alkaline triglyceride (TG) lipase activity above control levels in rat skeletal muscle. The second aim was to determine the effects of colchicine treatment on the concentration of TG in skeletal muscle. The results show that colchicine was a potent inducer of alkaline TG lipase activity, increasing enzyme activity approximately twofold in slow-twitch red, fast-twitch red, and fast-twitch white muscle types. It was found that in slow-twitch red soleus and fast-twitch red vastus, the two muscle groups with the highest levels of enzyme activity, 76% or more of enzyme activity resides in the intracellular compartment. These results provide evidence that colchicine blocks the export of alkaline TG lipase from skeletal muscle cells similar to that seen in the heart. The finding that TG were reduced at a time when enzyme activity was elevated suggests that intracellular alkaline TG lipase may be playing a role in the hydrolysis of the intramuscular TG droplet.

Animals↗
PubMed1978

Inhibition of mammary gland lactose secretion by colchicine and vincristine.

The possible role of microtubules in milk production was examined in mammary gland slices from lactating guinea pigs. Colchicine, 10(-5)-10(-4) M, depressed lactose secretion within 15 min, maintaining maximal inhibition over 2.5 h, accompanied by retention of lactose within the slices. In colchicine dose-response studies (2 h, 10(-8)-10(-5) M), secretion was depressed 22% by 10(-5) M, whereas tissue lactose increased with dose up to +25% at 10(-5) M. Lactose synthesis was inhibited 3-19% without correlation to colchicine concentration. In another study, incubation with 10(-5) M lumicolchicine yielded one-third less inhibition of secretion than 10(-5) M colchicine with no increase in tissue lactose. Both drugs depressed synthesis 31%. Lactose secretion showed a negative correlation with 10(-7)-10(-4) M vincristine yielding a maximal 66% inhibition at 10(-4) M, whereas tissue retention showed a linear increase with concentration up to 151% of control at 10(-4) M. Effects on synthesis were sporadic. These data suggest that microtubules have a role in facilitating the transport and/or secretion of lactose and perhaps other milk components.

Animals↗
PubMed1989

Colchicine-induced redistribution of an apical membrane glycoprotein (gp330) in proximal tubules.

Factors governing the selective, polarized insertion of membrane proteins are poorly understood, but some studies have suggested that microtubules are involved in the generation and maintenance of cell polarity. We have examined by immunocytochemistry the effect of the microtubule-disrupting agent, colchicine, on the cellular distribution of an endogenous glycoprotein, gp330, which is normally inserted only into the apical plasma membrane of proximal tubule epithelial cells. In control rats, gp330 was localized in the brush border and in apical invaginations and vesicles. Six hours after injection of colchicine, however, vesicles containing gp330 were dispersed throughout the entire cytoplasm of the cell. Many vesicles were packed into basolateral infoldings, close to the plasma membrane, but there was no significant insertion of gp330 into the basolateral membrane. When rabbit anti-gp330 antiserum was injected intravenously into colchicine-treated rats, immune complexes appeared in the glomerular basement membrane but could not be detected in peritubular basement membranes. This supports the conclusion that colchicine treatment does not result in the insertion of gp330 into the basolateral plasma membrane of proximal tubule cells. Our results indicate that although microtubules are involved in the accumulation of gp330-containing vesicles at the apical pole of the cell, other factors must be required for fusion with the plasma membrane to occur.

Animals↗
PubMed1999

Sustained JNK activation induces endothelial apoptosis: studies with colchicine and shear stress.

The disruption of microtubules by treating bovine aortic endothelial cells with 10(-7)-10(-5) M colchicine caused apoptosis, as evidenced by DNA laddering and TdT-mediated dUTP nick end labeling fluorescence staining. Colchicine treatment also induced a sustained activation of c-Jun NH(2)-terminal kinase (JNK) that lasted for >/=12 h. The blockade of JNK activity by using the negative interfering mutant JNK(K-R) markedly decreased the apoptosis induced by colchicine. Exposure of bovine aortic endothelial cells to laminar shear stress (12 dyn/cm(2)) caused a transient (<2 h) activation of JNK, and there was no induction of apoptosis. The sustained activation of JNK may play a significant role in the apoptosis induced by colchicine.

Animals↗
PubMed1998

Effect of colchicine on chronic ciclosporin nephrotoxicity in Sprague-Dawley rats.

Thirty male Sprague-Dawley rats were given ciclosporin (Cs) orally, 15 mg/kg daily for 80 days. Fifteen served as positive controls, while the other 15 were given daily colchicine at a dose of 30 microg/kg in addition to Cs. Additional 15 rats were given olive oil only and served as negative controls. The animals were subjected every other week to laboratory assessment of serum creatinine, sodium, potassium, and Cs whole-blood trough levels; also urine samples were examined for creatinine, sodium, potassium, and protein concentrations. At the end point, the animals were sacrificed, and kidney tissue was examined for histopathological changes. Comparing negative control versus Cs-treated and Cs-plus-colchicine-treated rats, there were no significant differences in serum creatinine, creatinine clearance, and serum and urine values of sodium and potassium as well as urinary protein/creatinine ratios. Yet histopathological examination of kidney tissues showed focal tubular atrophy and interstitial fibrosis in inner medulla and inner stripe of the outer medulla in all Cs-treated animals and in only 1 of the colchicine-treated group, but in none of the negative controls. Histological changes in other kidney zones in different animal groups were minor and not different. From this study, we may conclude that colchicine is of protective value against chronic Cs nephrotoxicity in Sprague-Dawley rats.

Animals↗
PubMed2004

Treatment of Pyoderma gangrenosum with low-dose colchicine.

Pyoderma gangrenosum (PG) is a neutrophilic dermatosis of unknown origin. Systemic agents occasionally administered provide either incomplete long-term control of the disease or have been associated with serious adverse side effects after chronic administration. We present two patients with PG successfully treated with low-dose colchicine. Antimitotic, anti-inflammatory and immunomodulating properties of colchicine might account for its beneficial effects in PG patients. Colchicine is effective and well tolerated in low doses by most patients. In addition, it is inexpensive and safer for long-term treatment than corticosteroids and other immunosuppressive agents. Colchicine may be proposed either as a single agent or as a corticosteroid-sparing agent for early treatment of PG.

Adult↗
PubMed1992

Effect of colchicine on ganglioside composition of rat primary culture neurons.

Developmental changes in gangliosides in the course of neurite outgrowth were examined in dissociated fetal rat cerebral neurons in culture. About a 2-fold increase in ganglioside levels was seen with the progression of neurite formation for up to 24 h in predominantly neuronal cultures. Ganglioside patterns appeared to be unchanged during the first 24 h, subsequently consisted of higher amounts of GD3 and b-series gangliosides (such as GD1b, GT1b, and GQ1b), and lower amounts of a-series gangliosides (GM1 and GD1a). Although the addition of colchicine to the cell growth medium inhibited neurite outgrowth in developing neurons, little if any differences in ganglioside patterns were found between control and colchicine-treated cells. Ganglioside levels decreased slightly in colchicine-treated cells in agreement with the decrease in cell attachment to culture dishes. Although colchicine treatment 8 h after plating caused complete retraction of formed neurites, the ganglioside level of the cells continued to increase during the following 16-hour incubation. Thus, the data suggest that ganglioside synthesis in differentiating neurons does not primarily accompany the expansion in cell surfaces due to neurite formation, and raises the possibility that a large proportion of gangliosides is retained in intracellular compartments.

Animals↗
PubMed1989

Morphological evidence of the formation of intracellular collagen fibrils in the embryonic mouse molar odontoblasts induced by colchicine administration.

The effects of colchicine on collagen formation were examined ultrastructurally using secretory odontoblasts in mouse molar tooth germs isografted to the spleen for 1 week. Colchicine in concentrations of 0.025 or 0.05 mg/0.1 ml was injected intravenously 12-24 h prior to harvesting. Colchicine induced the disruption of the Golgi apparatus and caused the accumulation of various types of Golgi-associated vacuoles containing collagenous fibrillar structures. Many vacuoles containing fine particles, nonstriated parallel filaments, banding patterns with a periodicity of approximately 63-nm intervals, and occasionally segment-long-spacing-like assemblies were aggregated in the cytoplasm during the experimental period. These morphological changes in vacuole contents may reflect the initial steps for polymerization of the intracellular collagen fibrils. The majority of the aggregated vacuoles were degraded by fusion with lysosomes but banded filamentous material in some vacuoles appeared to polymerize into the collagen fibrils with native structures. These results suggested that in unsecreted vacuoles accumulated in the odontoblasts as a result of colchicine administration the polymerization of collagen fibrils with native structures can occur.

Animals↗
PubMed1995

Effect of colchicine on schistosoma-induced renal amyloidosis in Syrian golden hamsters.

Seventy Syrian golden hamsters were infected with Schistosoma haematobium, and 10 uninfected hamsters served as negative controls. Of the schistosome-infected hamsters, 10 served as positive controls (infected but untreated) and the rest (60 hamsters) received treatment. In 30 hamsters treatment was given 9 weeks after infection (before the appearance of renal amyloidosis) and in the other 30 it was given after the appearance of amyloid deposits, 15 weeks after infection. Each treatment group was subdivided into 3 groups (10 hamsters each) in which treatment was either anti-schistosomal alone, combined anti-schistosomal and colchicine, or colchicine alone. Eighteen weeks after infection half of the animals in each group were sacrificed, while the rest were sacrificed 24 weeks after infection. Kidney specimens were evaluated semiquantitatively for renal amyloid deposits. Significant reductions in renal amyloid deposits and proteinuria were observed when combined treatment was given. This was nearly complete with early treatment and only partial when treatment was given late. When colchicine was given alone, a partial but significant reduction in proteinuria with no recognizable effect on renal amyloid deposits was observed. We conclude that colchicine is effective for the prevention and cure of schistosome-related renal amyloidosis in golden hamsters.

Amyloidosis↗
PubMed1976

Inhibition by ionophore A23187 of the cytotoxicity of vincristine, colchicine and X-rays to leukemic lymphocytes.

The ionophore A23187 was tested for its effect on the sensitivity of normal and leukemic lymphocytes to colchicine, vincristine, and X-irradiation. The ionophore was used because it transfers divalent cations through biological membranes and causes the transformation of normal lymphocytes. The sensitivity of the cells was measured by incubation of lymphocyte suspensions with and without reagent at 37 degrees C for one to seven days and counting the number of viable lymphocytes before and after incubation. Viability of the cells was judged by cytologic criteria as visualized by phase contrast microscopy. Lymphocytes were obtained from patients with chronic lymphocytic leukemia and from normal persons. Colchicine and vincristine killed in one day non-dividing leukemic lymphocytes while normal lymphocytes were much less sensitive to the two alkaloids. X-irradiation (1000 rad) killed nearly all leukemic lymphocytes in two days and normal lymphocytes in three days. Ionophore A23187 (2 X 10(-5)M) was moderately toxic to normal but not to leukemic lymphocytes and caused the transformation of both types of cells. The ionophore inhibited the cytocidal action of colchicine and vincristine to leukemic but not to normal lymphocytes and inhibited the action of X-irradiation to both types of lymphocytes. The present findings and a review of the literature suggest the hypothesis that calcium or other divalent ions are involved in the cytotoxicity of colchicine, vincristine, and X-irradiation of leukemic lymphocytes and that there may be an abnormality of the metabolism of divalent ions in leukemic lymphocytes.

Anti-Bacterial Agents↗
PubMed1995

Urological evaluation of Behçet patients and the effect of colchicine on fertility.

Behçet's disease is a multisystem disorder in which urogenital involvement mainly consists of genital aphthous ulcers, epididymitis, urethritis and recurrent cystitis. Colchicine is commonly used in these patients for the prevention of arthritic episodes. In this prospective study, 62 male patients under colchicine therapy for Behçet's disease underwent a complete urogenital evaluation. 33 (53.2%) had no urologic complaints. Physical examination revealed genital aphthous ulcers in 42 patients (67.7%) and epididymitis in 5 (8.1%). Analysis of urine specimens demonstrated proteinuria in 54.8% and hematuria in 30.6%. To establish any possible adverse effects of colchicine administration on male fertility, sperm analysis was performed: 23 patients (37.1%) had oligonecrospermia, 2 patients (3.2%) had azoospermia. Penile color flow Doppler sonography revealed arterial insufficiency in 17 patients (27.4%). Other urological findings were interpreted as coincidental. Our results indicate that urologic manifestations of Behçet's disease, and especially the possible adverse effects of colchicine administration on the reproductive potential of the treated patients should be carefully monitored.

Adult↗
PubMed1980

Platelets and microtubules. Effect of colchicine and D2O on platelet aggregation and release induced by calcium ionophore A23187.

We examined the role of microtubules in platelet aggregation and secretion (release reaction) induced by the calcium ionophore A23187 (0.8-5 muM). At these concentrations, platelet aggregation was preceded by a lag period of approximately 1 min. Colchicine (an agent that disrupts microtubule assembly-disassembly) was shown to bind to platelet microtubules by employing [(3)H]colchicine at a concentration that is specific for microtubules in other tissues (10 nM). Colchicine prolonged the lag period, inhibited the secondary wave of platelet aggregation, and inhibited the release reaction (release of [(14)C]serotonin). Platelets were next incubated with 20-60% D(2)O, an agent that stabilizes microtubules. D(2)O overcame colchicine-induced inhibition of the lag period, aggregation, and release. D(2)O alone enhanced platelet aggregation by 59+/-14% (SEM) and shortened the lag period by 43+/-10%. We conclude that functioning microtubules are required for platelet aggregation and release, and that microtubules of platelet preparations are functioning submaximally.

Adenosine Diphosphate↗
PubMed1993

Crystal-induced neutrophil activation. IV. Specific inhibition of tyrosine phosphorylation by colchicine.

We recently demonstrated that pathologically relevant inflammatory microcrystals, namely triclinic monosodium urate (MSU) and calcium pyrophosphate dihydrate (CPPD) crystals, potently stimulate a characteristic protein tyrosine phosphorylation pattern in human neutrophils that differed from that observed in response to other soluble or particulate agonists. In this study, the effects of colchicine on protein tyrosine phosphorylation induced by MSU and CPPD crystals in human blood neutrophils were investigated. Immunoblot analysis with antiphosphotyrosine antibodies demonstrated that colchicine dose-dependently inhibited the tyrosine phosphorylation of all the proteins phosphorylated in response to MSU and CPPD crystals. Other microtubule-disruptive agents such as vinblastine, nocodazole, and colcemid also inhibited crystal-induced protein tyrosine phosphorylation while lumicolchicine and trimethylcolchicinic acid were without effect. Indomethacin and phenylbutazone were similarly without effect on microcrystal-induced tyrosine phosphorylation. Colchicine, as well as the other active alkaloids, failed to inhibit the protein tyrosine phosphorylation elicited by FMLP, C5a, leukotriene B4, and unopsonized zymosan. Overall, these results demonstrate that colchicine specifically and significantly inhibits the protein tyrosine phosphorylation induced by MSU and CPPD crystals and suggest that its effects are associated, at least in part, with its interaction with microtubules. Furthermore, the use of microtubule-disrupting drugs demonstrate that the mechanisms implicated in the induction of protein tyrosine phosphorylation by microcrystals differed from those involved in response to other soluble or particulate agonists.

Blood Proteins↗