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PubMed1997

Interactions of a bicyclic analog of colchicine with beta-tubulin isoforms alphabeta(II), alphabeta(III) and alphabeta(IV).

Tubulin exists as various isoforms, which differ in their assembly, drug-binding properties, and the dynamic properties of the microtubules they compose. One of the most striking differences in drug binding among the isoforms is observed with colchicine, which binds much better to the alphabeta(II) and alphabeta(IV) isoforms than to the alphabeta(III) isoform. Here we have studied the interaction of these isoforms with 2-methoxy-5-(2',3',4'-trimethoxyphenyl) tropone (MTPT), an analog of colchicine that lacks the B-ring. The kinetics of association and dissociation were studied fluorometrically, and the kinetic parameters for the two-step binding were determined for different beta-tubulin isoforms. The apparent on-rate constants for alphabeta(II), alphabeta(III) and alphabeta(IV) were 13358, 4558 and 10828 M(-1) s(-1), the off-rate constants (k(-2)) were 0.04, 0.03 and 0.02 s(-1), and the affinity constants are 3.33 x 10(5), 1.56 x 10(5) and 5.44 x 10(5) M(-1), respectively. The differences in kinetic parameters among different beta-tubulin isoforms are greatly reduced when the B-ring is removed. Our results indicate that the B-ring plays a major role in determining the isoform differences, and the results might be of importance for designing tissue-specific analogs of colchicine for cancer chemotherapy.

Colchicine↗
PubMed1989

Colchicine-induced inhibition of fat globule development in hepatocytes of rats injected with ethionine.

To examine the effect of colchicine on ethionine-induced fatty liver, adult female rats were starved overnight and then injected i.p. with 1 g/kg ethionine at 11th hour of fasting; then a half of the rats were also injected i.p. with 2.5 mg/kg colchicine twice at 3 and 6 h after the single administration of ethionine. Similarly, fasted control rats were injected i.p. with vehicle alone at the above times. All of the rats were sacrificed after a 20-h fast, and the hepatocytes in periportal areas were observed ultrastructurally. In addition, total lipids in the liver tissue were extracted and determined biochemically. Although similar significant increases of triglyceride were observed in the liver tissue of all ethionine-injected rats, the hepatocytes in the group treated with both chemicals had fewer cytoplasmic fat globules (CFG) than those in the group treated with ethionine only. On the other hand, the diameters of markedly increased membrane-bound lipid particles (MLP) in the double-treated group were distributed mainly in the range 0.2-0.4 micron, compared with those (0.1-0.2 micron) in the other groups. These findings indicate that colchicine inhibits the development of CFG in ethionine-injured hepatocytes.

Animals↗
PubMed1980

The effect of colchicine and cytochalasin B on the release of taurine from the chick retina.

The effect of colchicine (0.5 mM) and of cytochalasin B (10(-4) M) on the release of [35S]taurine from the isolated chick retina, upon stimulation by 68.5 mM-KCl, 10(-5) M-veratridine, and 10 mM-glutamate, was studied. Cytochalasin and colchicine effects on taurine release were compared with those on K+-stimulated release of [3H]dopamine and [3H]GABA. Colchicine caused a marked decrease of the [35S]taurine release evoked by the three stimulatory agents; it also decreased [3H]dopamine release without affecting that of [3H]GABA. Cytochalasin B significantly decreased the efflux of [35S]taurine stimulated by glutamate or veratridine without altering that evoked by 68.5 mM-KCl. Cytochalasin practically suppressed the [3H]dopamine-stimulated release and slightly decreased that of [3H]GABA. This drug produced a high increase in the spontaneous release of labeled GABA and taurine. These results suggest that the release of taurine and GABA from the chick retina probably occurs though different mechanisms. It is suggested that taurine release may be related to a process involving contractile proteins.

Animals↗
PubMed1986

Altered colchicine-binding capacity in chick brain regions: relationship to intensity or information content of visual input.

The binding of [3H]colchicine to postmitochondrial supernatant fractions of chick brain has been studied, absorbing colchicine-bearing proteins on DEAE-cellulose filter discs. This was assayed at several times after unilateral enucleation of day-old chicks. Binding was unaltered in optic lobes or anterior dorsal forebrain regions contralateral to the removed eye, relative to the corresponding regions contralateral to and thus directly or secondarily innervated by the intact eye. Colchicine binding was also assayed after training chicks to suppress pecking at a metallic bead coated with aversive-tasting methylanthranilate. At 4 but not 24 h after the one-trial training, binding was selectively elevated in the anterior dorsal forebrain roof. Results are taken to imply that alterations in tubulin content of chick brain may reflect stress-related changes, possibly mediated by systemic endocrine flux, rather than a more localized learning experience.

Animals↗
PubMed1978

Time course of degeneration of short and long postganglionic sympathetic nerve fibres and effect of pentobarbitone and colchicine on degeneration.

1 The time-course of degeneration of sympathetic nerves was investigated by measurement of the endogenous noradrenaline content of the rat vas deferens, submandibular gland and spleen following sympathectomy.2 Extirpation of the hypogastric plexus, superior cervical ganglion and coeliac plexus under pentobarbitone anaesthesia caused 50% depletion of the noradrenaline content of the vas deferens, submandibular gland and spleen in approximately 16, 19 and 21 h, respectively.3 Under pentobarbitone anaesthesia, proximal sympathectomy (i.e., close to the end organ) produced depletion of the noradrenaline content of the submandibular gland 8 h earlier than that caused by distal sympathectomy. Under ether anaesthesia, the time difference in obtaining the same degree of depletion after the two procedures of sympathectomy was only 2 hours.4 Removal of the superior cervical ganglion under ether anaesthesia resulted in almost complete depletion of noradrenaline content of the submandibular gland in 17 h, whereas when a similar operation was performed under pentobarbitone anaesthesia, nearly 24 h were required for the same degree of depletion. Similarly, the noradrenaline content of the spleen was depleted 4 h earlier if the coeliac plexus was ablated under ether as compared to pentobarbitone anaesthesia.5 Local application of colchicine (10 mg/ml, 30 min) to postganglionic sympathetic nerve axons had no effect on the noradrenaline content of the submandibular gland up to 24 hours. However, removal of the superior ganglion following colchicine application considerably slowed the depletion of the noradrenaline content of the submandibular gland (at 17 and 20 h after ganglionectomy, 10 and 20% depletion, respectively, in the experimental gland, as compared to 70 and 80%, respectively, in the control gland).6 To explain the results, it is proposed that injury to the sympathetic nerves at the site of sectioning triggers a signal (messenger substance) which travels down to the nerve endings to produce degeneration. Thus, the length of the extrinsic nerve fibre influences the time course of degeneration by changing the rate of transport of the messenger substance, whereas pentobarbitone and colchicine alter the synthesis and/or transport of the messenger substance to modify the time-course of degeneration.

Animals↗
PubMed1979

Action of colchicine and cytochalasin B on the acetylcholine receptor.

1. The effects of colchicine and cytochalasin B have been investigated on the extrajunctional acetylcholine (ACh) receptors of rat muscle. 2. Colchicine and cytochalasin B each decreased the amplitude and rise time of the iontophoretic ACh potential. When the dose of ACh was increased in the presence of these agents, ACh potentials were produced with a biphasic waveform consisting of a fast initial phase and a second slow phase. 3. It is proposed that colchicine and cytochalasin B are acting through a mechanism other than the breakdown of microtubules and microfilaments.

Acetylcholine↗
PubMed1978

Effect of colchicine on cell membrane and on biopterin transport in Crithidia fasciculata.

Incorporation of 14C-labeled biopterin into Crithidia fasciculata was inhibited by 1 mM colchicine or lumicolchicine. These substance do not penetrate the cell membrane, hence they cannot interact with the subpellicular microtubules. In view of this, interference of colchicine with biopterin transport must occur on the outer surface of the cell membrane. Binding of colchicine to Crithidia was not temperature-dependent and did not exhibit saturation kinetics. These facts exclude a binding as in the case of tubulin, or similar proteins which may be present in the membrane. The results suggest an inhibition reflecting steric hindrance of the biopterin carrier system.

Animals↗
PubMed1986

Effect of colchicine, vinblastine, and cytochalasin B on cell surface anionic sites of Tritrichomonas foetus.

Drugs that interact with microtubules (colchicine and vinblastine) and microfilaments (cytochalasin B) partially inhibited cell growth and motility of Tritrichomonas foetus. Parasites incubated with these substances became rounded and cell division was blocked. Neither colchicine nor vinblastine disrupted the microtubules that form the peltar-axostylar system. Any one of these drugs interfered with the net negative surface charge of T. foetus as evaluated by determination of the cellular electrophoretic mobility (EPM). The decrease in the EPM of cytochalasin B-treated cells was caused by dimethylsulfoxide, which was used as solvent. Untreated cells as well as cytochalasin B-treated cells showed a uniform distribution of anionic sites on the plasma membrane as seen with cationized ferritin particles. In cells treated with colchicine or vinblastine the anionic sites were distributed in patches. These results are discussed in terms of participation of labile cytoplasmic microtubules and microfilaments in the control of the distribution of anionic site-containing macromolecules located on the cell surface of T. foetus.

Animals↗
PubMed1994

Effects of phalloidin and colchicine on diethylmaleate-induced choleresis and ultrastructural appearance of rat hepatocytes.

Diethylmaleate is used as a model compound whose glutathione conjugates are secreted into bile, and which induce choleresis and the formation of Golgi-derived vesicles in hepatocytes. This study was performed to test the assumption that these vesicles are involved in the bile canalicular secretion of diethylmaleate. We reasoned that phalloidin and colchicine, two drugs acting on microfilaments and microtubules, respectively, can modify the movements of diethylmaleate-induced vesicles towards the bile canaliculus. Phalloidin induced the formation of a thick microfilamentous network around the bile canalicular plasma membrane domain. A significant decrease in diethylmaleate-stimulated choleresis was observed, associated with a striking accumulation of pericanalicular vesicles, which were confirmed by morphometric analysis. In contrast, in rats pretreated with colchicine, after diethylmaleate administration, only a few vesicles were observed around the bile canaliculus, while diethylmaleate-induced choleresis also decreased. These results suggest that: a) the thick microfilament network induced by phalloidin prevents diethylmaleate-associated vesicles reaching the bile canalicular plasma membrane; and b) colchicine produces a dispersion of these vesicles in the cytoplasm of hepatocytes by inhibiting the polymerization of microtubules. These observations support a role of vesicles in the transport of diethylmaleate by hepatocyte into bile, and are consistent with the existence of a vesicular pathway for the biliary secretion of diethylmaleate and possibly other organic anions.

Animals↗
PubMedDate not supplied

Colchicine treatment in conception and pregnancy: two hundred thirty-one pregnancies in patients with familial Mediterranean fever.

The effect of maternal use of colchicine on fetuses is unknown. The children of 116 women with Familial Mediterranean Fever (225 completed pregnancies) were studied. There was no unusual frequency of fetal abnormality among women taking colchicine before or during pregnancy. Colchicine treatment does not apparently harm mother or child.

Abnormalities, Drug-Induced↗
PubMed1980

Late effects of colchicine on the bursa of Fabricius after neonatal application on the anal lips of chickens.

One week after the application of colchicine on the anal lips of chickens, the bursa of Fabricius was devoid of lymphoid cells and contained only a few epithelial buds, all of which were later repopulated with lymphoid cells to form mature lymphoid follicles. After the intraperitoneal injection of cyclophosphamide, numerous epithelial buds were found in the bursa, and at the age of six weeks only a few of them were populated with lymphoid cells. On week 6, the bursal weights of the chickens treated with colchicine were only about 10% of the normal, and about 80% of the bursal weights of the cyclophosphamide-treated chickens. The colchicine treatment affected the morphology of the spleen less than the treatment with cyclophosphamide. It is concluded that this new model of chemical bursectomy differs distinctly from the cyclophosphamide model and therefore serves as a new tool in studying bursal function in chicken.

Anal Canal↗
PubMed1976

Effects of colchicine and vinblastine on axonal transport of choline acetyltransferase in rat sciatic nerve.

The effects of colchicine (0.5-10(-2) M) and vinblastine (10(-2)-10(-5) M) Upon axonal transport of choline acetyltranserase (CAT) and on nerve impulse conduction have been investigated in the rat sciatic nerve. High concentrations of colchicine (0.5 M) and vinblastine (10(-2) M) blocked completely both axonal transport of CAT and impulse conduction. 10(-3) M vinblastine did not affect impulse conduction until 20-22 h after injection, but this concentration of vinblastine did block CAT transport but not impulse conduction. 10(-2) M and 10(-1) M colchicine were without effect on impulse conduction, but did produce substantial, although incomplete, block of CAT transport. The results are discussed in relation to the possible involvement of microtubules in transport of CAT.

Acetyltransferases↗
PubMed1992

Synthesis and evaluation of 2-diazo-3,3,3-trifluopropanoyl derivatives of colchicine and podophyllotoxin as photoaffinity labels: reactivity, photochemistry, and tubulin binding.

Derivatives of the tubulin polymerization inhibitors colchicine and podophyllotoxin bearing the photoreactive 2-diazo-3,3,3-trifluoropropanoyl (DTFP) group were synthesized for evaluation as potential photoaffinity labels of the tubulin binding site. All labels were assayed for their ability to inhibit tubulin polymerization, and N-DTFP-deacetylthiocolchicine was shown to competitively inhibit tubulin-colchicine binding with a Ki of 4-5 microM. The tubulin off-rate of this analog was similar to that of podophyllotoxin, rather than to the relatively irreversibly bound colchicine. Photochemical solvent insertion reactions of the labels were investigated. Radioactive samples of the two most active labels were prepared and used in initial protein-labeling experiments, during which the fractional occupancy of tubulin and extent of covalent incorporation were determined. A rearrangement of DTFP amides was encountered which is relevant to the utility of this moiety for use in synthesis of photoaffinity labels.

Affinity Labels↗
PubMed1985

Influence of colchicine on the healing of corneal endothelium.

The healing of a corneal endothelial defect involves cell division and cell migration. Microtubuli form the spindle-fibers and parts of the cytoskeleton, and may therefore play a role in these cellular processes. In the present study colchicine is used in tissue culture to inhibit the assembly of microtubuli. Colchicine causes not only an arresting effect on cell division in the metaphase, but also an inhibitory effect on the cell migration. This latter effect is demonstrated by the radially directed, spindle-shaped cells seen in the repair zone of the control corneas being replaced by flat rounded cells. In this respect, in the presence of colchicine, the corneal endothelial cells behave like fibroblasts and not like epithelial cells.

Animals↗
PubMed1980

The effects of colchicine on milk secretion, mammary metabolism and blood flow in the goat.

Mammary function in the conscious goat was studied during colchicine-induced depression of milk secretion in one mammary gland. Milk yield of the treated gland was reduced to approximately a quarter of previous, while there were significant increases in afternoon milk yield from the untreated glands on the 2nd and 3rd days after treatment in goats in late lactation. Milk composition in the untreated glands was not significantly affected. In the treated gland, milk [Na+], [Cl-], [citrate] and [protein] increased while [K+] and [lactose] decreased, although the time course of these changes differed; milk [fat] was unaffected. Mammary extractions ((A-V)/A) of glucose, acetate and most amino acids were significantly decreased during the period of maximal inhibition of secretion. There were no significant changes in arterial plasma concentrations of glucose, acetate or any essential amino acids. In another series of experiments, mammary blood flow increased and then returned to normal after colchicine treatment even though milk yield and mammary glucose uptake decreased markedly; oxygen uptake was not significantly affected. The results are discussed in relation to the actions of colchicine on the mammary secretory cell, to the normal control of mammary blood flow and to the mechanism of compensation by the untreated gland.

Animals↗
PubMed1971

Studies on the translocation of noradrenaline-containing vesicles in post-ganglionic sympathetic neurones in vitro. Inhibition of movement by colchicine and vinblastine and evidence for the involvement of axonal microtubules.

1. Methods are presented for studying axonal transport mechanisms in preparations of constricted hypogastric nerve/inferior mesenteric ganglia maintained in vitro for periods up to 48 hr. Under these conditions the ultrastructure of the tissue is excellently preserved.2. The proximo-distal movement of noradrenaline and noradrenaline storage vesicles in the non-myelinated axons of these preparations is inhibited by both colchicine (10 mug/ml.) and vinblastine sulphate (1 mug/ml.) whilst the movement of mitochondria appears to be unaffected.3. Neither colchicine nor vinblastine sulphate depletes accumulated dense-cored vesicles of their stores of noradrenaline.4. These drugs reduce the accumulation of noradrenaline and densecored vesicles against a constriction when they are in contact with the nerve trunks only, and are denied direct access to the nerve cell bodies in the ganglion.5. The only other morphological change that can be attributed to the action of colchicine and vinblastine is a marked reduction in the number of axonal microtubules.6. The experiments provide strong support for the view that the axonal system of microtubules is closely involved in the proximo-distal movement of noradrenaline storage vesicles within noradrenergic neurones. The microtubular system does not appear to be involved in mitochondrial movement.

Animals↗
PubMed1980

Renin release from isolated rat glomeruli: effects of colchicine, vinca alkaloids, dimethylsulphoxide, and cytochalasins.

1. Preparations of isolated glomeruli were superfused and the effects of colchicine, the vinca alkaloids, and the cytochalasins A, B, D, and E investigated on basal renin release and the response of the glomeruli to osmotic stress. 2. Colchicine (10(-3) M) had no effect, whereas vinblastine and vincristine (10(-5) M) caused a progressive increase in basal renin release from isolated glomeruli. 3. After 60 min exposure to either colchicine or the vinca alkaloids, the first renin release response to a hypoosmotic challenge (reduction in sucrose or sodium chloride concentration) was depressed while that of the second (after 120 min exposure) was enhanced. 4. Addition of 0.5% dimethylsulphoxide (DMSO) and each of the cytochalasins A, B, D, and E (5 micrograms/ml.) had no significant effect on basal renin release. 5. DMSO (0.5%) depressed the release response to the first 20 m-osmole/kg reduction in medium osmolality obtained by lowering the sucrose concentration. This effect had vanished at the time of the second 20 m-osmole stimulus (120 min). 6. The normal response to the first 30 m-osmole/kg reduction in NaCl concentration (and medium osmolality) was abolished by 0.5% DMSO. Rather, a depressed release compared to unstimulated control experiments was observed. The response to the second stimulus in the presence of DMSO was about half that of control experiments. 7. Following the first hypoosmotic stimulus (by lowering the concentrations of sucrose of NaCl) the cytochalasins A, B, D and E (5 micrograms/ml.) caused an increased release of renin which persisted throughout the length of the experiment. The cytochalasins used were equally potent in this respect. 8. The results are in agreement with previous findings, suggesting that renin release from the juxtaglomerular cells adhering to isolated glomeruli is mediated through a mechanism different from exocytosis.

Animals↗
PubMed1972

Axotomy mimicked by localized colchicine application.

Comparable depression of synaptic transmission in the avian ciliary ganglion resulted from either section or localized colchicine treatment of the ciliary nerves. Both colchicine treatment and axotomny produced similar changes in RNA distribution in the cell bodies as well. Colchicine did not directly affect transmission, and action potential propagation along the ciliary nerves was normal. Interference with axoplasmic transport of material in both cases is postulated to signal the observed chromatolytic changes.

Action Potentials↗