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PubMed1989

Specific, high affinity colchicine binding monoclonal antibodies: development and characterization of the antibodies.

Nine colchicine specific monoclonal antibodies have been developed by immunizing BALB/c mice with a colchicine-keyhole limpet hemocyanin (Col-KLH) conjugate prepared using a bishydroxysuccinimide coupling reagent. Of four immunization procedures examined, intraperitoneal injection of the antigen attached to acid treated E. coli resulted in the maximum antigen specific antibody titers. A colchicine bovine serum albumin (Col-BSA) conjugate, prepared using a water soluble carbodiimide coupling technique, formed the basis of an enzyme linked immunosorbent assay used for screening hybridomas for colchicine specific antibody secretion and for determining the relative affinity and specificity profile of the monoclonal antibodies. All antibodies demonstrated high affinity, saturable binding to colchicine and low cross-reactivity with a panel of compounds structurally related to colchicine. The IC50 for the highest affinity antibody, C44, was 3.6 +/- 0.84 nM colchicine in the competitive enzyme immunoassay. The affinity of this antibody determined from Scatchard analysis of antibody binding to tritiated colchicine was 0.66 +/- 0.11 nM. Antibody C44 has the level of specificity and affinity suitable for a sensitive and selective immunoassay of colchicine for monitoring therapeutic drug levels. In addition, this antibody provides a specific pharmacologic antagonist for studies of colchicine's therapeutic mechanism and has the potential to reverse colchicine toxicity.

Animals↗

PubMed1997

Encapsulation, stability and in-vitro release characteristics of liposomal formulations of colchicine.

The severe toxicity and low therapeutic index of colchicine limit its therapeutic use. Encapsulation in liposomes might reduce these toxic effects. The objective of this study was to determine the factors influencing encapsulation of colchicine in liposomes and to optimize the encapsulation parameters. Colchicine was encapsulated in multilamellar liposomes and large unilamellar liposomes prepared using various phospholipids. The effects of method of preparation, type of vesicle, charge, and concentration of cholesterol on encapsulation of colchicine in liposomes were investigated. Also, stability of colchicine under stress conditions and at various temperatures, and in-vitro release characteristics were determined. A significant difference in encapsulation of colchicine in multilamellar liposomes was observed when prepared by two different methods. Induction of charge on the liposome surface increased encapsulation of colchicine in multilamellar liposomes, but did not affect large unilamellar liposomes. The liposome preparations could withstand simulated transport conditions and frequent changes in temperature. Particle size and concentration of colchicine did not change significantly during storage at various temperatures for six months. In order to retain encapsulated colchicine in liposomes, storage at or below room temperature was found to be suitable. In-vitro release of colchicine from large unilamellar liposomes was biphasic and was influenced by two rate-limiting barriers, the dialysis membrane and the liposome bi-layers. For optimum encapsulation and stability of colchicine liposomes were prepared from a mixture of 1,2-distearoyl-sn-glycero-3-phosphocholine, cholesterol and either stearylamine or dicetyl phosphate.

Capsules↗

PubMed2004

Acute colchicine intoxication during clarithromycin administration.

OBJECTIVE: To report a case of colchicine intoxication occurring with institution of clarithromycin. CASE SUMMARY: A 76-year-old man with familial Mediterranean fever (FMF) had received colchicine 1.5 mg daily for 6 years. The patient underwent 7 days of clarithromycin, amoxicillin, and omeprazole treatment for Helicobacter pylori-associated gastritis. Fever, abdominal pain, and diarrhea occurred 3 days after treatment initiation. On day 8, dehydration, pancytopenia, metabolic acidosis, and increased lipase level necessitated hospitalization. Alopecia was observed 2 weeks later. The patient recovered fully after the colchicine dosage was reduced to 0.5 mg/day and rehydration was performed. The previous dosage was then reinstituted without adverse reaction. An objective causality assessment revealed that the adverse event was probable. DISCUSSION: Continuous colchicine administration is used in treatment of microcrystalline arthritis, Behcet's disease, and FMF. Colchicine is primarily eliminated through biliary excretion. Renal elimination and cytochrome P450 metabolism play a less significant role. Colchicine is also a substrate of P-glycoprotein, a transporter involved in cellular efflux and elimination of numerous drugs. Three cases of intoxication have been reported when colchicine was combined with erythromycin, josamycin, or clarithromycin. Macrolides are inhibitors of P-glycoprotein and cytochrome P450-dependent enzymes and may decrease colchicine's biliary excretion through P-glycoprotein inhibition. CONCLUSIONS: Coadministration of colchicine and macrolides may impair colchicine elimination, resulting in excess drug exposure and toxicity. To this end, colchicine should be used with extreme caution in patients receiving P-glycoprotein inhibitors, particularly if they are elderly and/or renally compromised.

Aged↗

PubMed1996

A comprehensive investigation of inpatient intravenous colchicine use shows more education is needed.

OBJECTIVE: To test the hypothesis that colchicine therapy for patients in whom treatment was guided by rheumatology consultation was more appropriately prescribed than therapy for patients not receiving consultation. METHODS: A retrospective chart review of all inpatients with acute crystal induced arthritis who received intravenous (iv) colchicine was performed to assess iv colchicine prescribing errors and any adverse outcomes of iv colchicine therapy. RESULTS: Errors in the prescribing of iv colchicine occurred in 5 of 19 patients (26%). A rheumatology consultation was not obtained in any of these cases. Overall, there was a significant increase in the prescribing error rate in the no-consultation versus the consultation groups (p = 0.045). These 5 errors did not lead to serious adverse outcomes, but leukopenia occurred in one patient and the white blood cell count decreased from 7.3 to 4.3 cells/mm3 in another patient. Leukopenia also occurred in 3 patients in whom iv colchicine was used appropriately. CONCLUSION: (1) Previously published guidelines for iv colchicine use appeared successful at preventing serious colchicine toxicity. (2) These guidelines do not protect against leukopenia occurring from colchicine use. (3) Rheumatology consultation may help prevent errors in the use of iv colchicine. (4) Further education is needed in the correct use of iv colchicine.

Adult↗

PubMed1988

Treatment of brachial nerves with colchicine inhibits limb regeneration in the newt Notophthalmus viridescens.

In urodele amphibians, limb regeneration is dependent on innervation and is blocked by the administration of colchicine. The objective of this experiment was to determine if colchicine blocks limb regeneration by a direct action on the blastema cells or by an indirect action on the nerves, specifically, if colchicine treatment of the brachial nerves would inhibit limb regeneration in the newt Notophthalmus viridescens. Colchicine was applied to the nerves by implanting a colchicine-loaded silastin block adjacent to the brachial nerves of an amputated newt limb. With appropriate dose levels of colchicine, limb regeneration was completely inhibited. Contralateral control limbs, carrying unloaded silastin blocks, and control limbs with colchicine-loaded blocks implanted equidistant from the blastema, but not adjacent to the brachial nerves, regenerated normally. Thus, the results indicate that the colchicine inhibition of limb regeneration is mediated by colchicine effects on the nerves. The possible mechanism of colchicine action on nerves may involve either wallerian degeneration, or inhibition of axoplasmic transport, or both.

Animals↗

PubMed1991

Interactions of colchicine with tubulin.

Colchicine exerts its biological effects through binding to the soluble tubulin heterodimer, the major component of the microtubule. The colchicine-binding abilities of tubulins from a variety of sources are summarized, and the mechanism of colchicine binding to brain tubulin is explored in depth. The relationship between colchicinoid structure and tubulin binding activity provides insight into the structural features of colchicine responsible for high affinity binding to tubulin and is reviewed for analogs in the colchicine series. The thermodynamic and kinetic aspects of the association are described and evaluated in terms of the binding mechanism. Colchicine binding to tubulin results in unusual alterations in the low energy electronic spectra of colchicine. The spectroscopic features of colchicine bound to tubulin are discussed in terms of the nature of the colchicine-tubulin complex. Attempts to locate the high affinity colchicine binding site on tubulin are presented.

Animals↗

PubMed1995

[Colchicine: recent data on pharmacokinetics and clinical pharmacology].

Colchicine is widely used in the treatment of acute goutty arthritis. Recently, colchicine was shown to be effective in inflammatory diseases such as familial Mediterranean fever. Two proteins can modulate its pharmacokinetics: tubulin, the specific intracellular receptor for colchicine which determines the plasma half-life, and P-glycoprotein, an active efflux pump towards some anticancer drugs which regulates colchicine absorption, distribution, and elimination. Therapeutic dosage is monitored empirically, by the control of the balance between the occurrence of side effects and the clinical efficacy. Recently, using a specific and sensitive radioimmunoassay, the investigation of plasma concentrations during single and multiple dose studies has allowed to define the colchicine pharmacokinetic parameters. Following oral route, colchicine bioavailability is extremely variable (from 24 to 88% of the administered dose), the distribution volume is elevated (7 l/kg) but the binding to albumin is moderate. Colchicine elimination occurred mainly via hepatic pathways and the elimination half-life ranged from 20 to 40 hours. In multiple dose study (1 mg/d), the steady-state is reached 8 days after the first oral administration and plasma concentrations ranged from 0.3 to 2.5 ng/ml. Pharmacokinetic/pharmacodynamic studies show that the biological effects of colchicine were not related to plasma concentrations but with intraleukocyte concentrations. Drug interactions may occur when colchicine is associated to drugs which interact with cytochrome P450 and/or P-glycoprotein and modify renal and/or hepatic clearances. The therapeutic drug monitoring of colchicine during these circumstances could allow to prevent the observation of side effects.

Biological Availability↗

PubMed1989

Colchicine binding in the free-living nematode Caenorhabditis elegans.

The [3H]colchicine-binding activity of a crude supernatant of the free-living nematode Caenorhabditis elegans was resolved into a non-saturable component and a tubulin-specific component after partial purification of tubulin by polylysine affinity chromatography. The two fractions displayed opposing thermal dependencies of [3H]colchicine binding, with non-saturable binding increasing, and tubulin binding decreasing, at 4 degrees C. Binding of [3H]colchicine to C.elegans tubulin at 37 degrees C is a pseudo-first-order rate process with a long equilibration time. The affinity of C. elegans tubulin for [3H]colchicine is relatively low (Ka = 1.7 x 10(5) M(-1)) and is characteristic of the colchicine binding affinities observed for tubulins derived from parasitic nematodes. [3H]Colchicine binding to C. elegans tubulin was inhibited by unlabelled colchicine, podophyllotoxin and mebendazole, and was enhanced by vinblastine. The inhibition of [3H]colchicine binding by mebendazole was 10-fold greater for C. elegans tubulin than for ovine brain tubulin. The inhibition of [3H]colchicine binding to C. elegans tubulin by mebendazole is consistent with the recognised anthelmintic action of the benzimidazole carbamates. These data indicate that C. elegans is a useful model for examining the interactions between microtubule inhibitors and the colchicine binding site of nematode tubulin.

Animals↗

PubMed2005

Fibroblast heterogeneity in collagenolytic response to colchicine.

Matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) are important in various physiological and pathological conditions, including those that involve homeostasis of collagen. Drug induced regulation of MMP-1, other MMPs and TIMPs is critical in treatment of various diseases, e.g. the use of the plant alkaloid, colchicine. One possible factor that might explain the failure in colchicine-treatment of some patients is interindividual variability on the cellular level. To investigate the possible individual heterogeneity in response to colchicine, we studied the effect of colchicine-induced synthesis of collagenase from 32 different human skin fibroblast strains derived from both healthy individuals as well as individuals with different skin diseases. We showed that colchicine induced an increased synthesis of collagenase in 22 of 32 cases. This heterogeneity occurred in fibroblasts from healthy as well as diseased individuals. To determine if colchicine also affected the fibroblast synthesis of gelatinase, stromelysin and tissue inhibitors of MMPs, we investigated several individuals from a single family. The results showed that both colchicine responsive and non-responsive fibroblasts with respect to collagenase synthesis responded to colchicine by an increased stromelysin synthesis, while the synthesis of gelatinase and TIMP-1 were unaffected. As a whole, our results indicate that individual heterogeneity in collagenase response to colchicine treatment may partly explain some of the controversial results obtained with colchicine as a drug.

Case-Control Studies↗

PubMed1998

Simultaneous microdialysis in brain and blood of the mouse: extracellular and intracellular brain colchicine disposition.

A simultaneous brain and blood microdialysis system was developed to study the passage of colchicine through the blood-brain barrier in the mouse. Colchicine was administered as a bolus in the jugular vein (1.5 mg kg-1) and its hippocampal extracellular fluid (ECF) and blood kinetics were determined over a 4 h period using two microdialysis probes, one in the dorsal hippocampus, the other in the inferior vena cava. Colchicine rapidly diffused into the hippocampus (maximum concentration in the first dialysate sample) and brain and blood concentrations declined in parallel, suggesting rapid equilibration between these two compartments. However, only 6. 7% of total blood colchicine, 14% of unbound colchicine was present in the hippocampus suggesting that the P-glycoprotein efflux pump limits colchicine uptake by the brain. We also found, using conventional tissue homogenate analysis in parallel, that the concentration of colchicine in the hippocampal ECF was 10 times less than that in the intracellular space and that the hippocampus colchicine concentration was 2.8 times higher than that of the rest of the brain. This study shows that the simultaneous brain and blood microdialysis can be used to measure the passage of colchicine through the blood-brain barrier and to estimate the brain extra- and intracellular distribution of colchicine.

Animals↗

PubMed1998

Colchicine: 1998 update.

OBJECTIVE: To present an update of the use of colchicine in patients with familial Mediterranean fever (FMF) and other rheumatic and nonrheumatic diseases. DATA SOURCES: Published studies on colchicine retrieved from MEDLINE searches from 1987 to 1997 and reports presented at national and international meetings. STUDIES SELECTION AND EXTRACTION: All studies were reviewed by the authors. Reports addressing the topics of colchicine pharmacokinetics, biological effects, indications for use, and side effects were selected. DATA SYNTHESIS: Colchicine is an alkaloid that may interfere with microtubule formation, thereby affecting mitosis and other microtubule-dependent functions. It has a bioavailability of 25% to 50% when administered orally. Colchicine and its metabolites are excreted through the urinary and biliary tracts. It may be used while breast feeding; however, amniocentesis should be performed when used in pregnancy. The drug may be given to children with FMF. The efficacy of colchicine has been proved in FMF, gout, Behcet's disease, and cirrhosis. Its place in the treatment of scleroderma, sarcoidosis, and skin disorders remains to be determined. Gastrointestinal side effects occur early and are most common manifestations of colchicine toxicity. Severe colchicine toxicity results in multiple organ failure, convulsions, coma, and death. Potentially, effective treatment with Fab anti-colchicine antibodies unfortunately is unavailable; therefore, treatment is supportive. CONCLUSIONS: Colchicine is a relatively safe and effective medication for several disorders when used in appropriate dosage in patients with normal kidney and liver function.

Behcet Syndrome↗

PubMed1972

Colchicine-binding protein and the secretion of thyroid hormone.

The role of microtubules in the thyrotropin- or adenosine 3',5' cyclic monophosphate (cyclic AMP)-stimulated accumulation of cytoplasmic colloid droplets and secretion of iodine from the mouse thyroid gland has been investigated by means of different classes of agents that affect the stability of microtubules. The onset of inhibition of secretion by colchicine, the uptake of colchicine-(3)H by thyroid lobes, and the binding of colchicine-(3)H to thyroidal soluble protein are shown to have similar time courses Colloid droplet accumulation is also inhibited and does not readily resume upon removal of colchicine from the medium. This appears to be due to the slow washout of the drug (t((1/2)) approximately hr). Thyroids contain a soluble colchicine-binding protein that resembles microtubule proteins of other tissues with respect to apparent K(m) for colchicine, pH optimum, and stability characteristics Colchicine analogues inhibit iodine secretion and colchicine binding in a parallel manner and as a function of their antimitotic potencies. Microtubule-stabilizing agents such as hexylene glycol and D(2)O also inhibit secretion. Thus, inhibition of thyroid secretion by antimitotic agents appears to be mediated by an effect on microtubules. The inhibitory locus of colchicine inhibition occurs after the generation of cyclic AMP, since stimulation of secretion by this nucleotide is blocked by colchicine, whereas thyroid-stimulating hormone-induced accumulation of cyclic AMP is not affected. Thus, the functioning microtubule appears to play a role in the induction of colloid endocytosis.

Animals↗

PubMed1997

Colchicine myopathy in renal transplant recipients on cyclosporin.

Few data are available about the muscle status in renal transplant recipients. Moreover, the list of myotoxic drugs is growing longer and some of them are likely to be prescribed in renal transplant patients. These conditions may act as confounding factors in case reports of both cyclosporin and colchicine myopathies. Moreover no study has evaluated the frequency of myopathy in patients on both colchicine and cyclosporin. We conducted a retrospective study including all renal transplant recipients followed in our unit in whom colchicine was prescribed since January 1994. Clinical and biological data of patients on both colchicine and cyclosporin were analysed. Secondly case subjects were compared with matched controls not receiving colchicine but cyclosporin. Ten patients received colchicine in association with cyclosporin. Five patients (50%) experienced muscular symptoms and when performed, muscular histology showed vacuolar myopathy. All five patients improved after colchicine withdrawal. Cases with and without muscular symptoms did not differ in age, transplant duration, and serum creatinine level. Mean duration of colchicine therapy was 12.2 +/- 4.4 months in cases with muscular symptoms and 6.8 +/- 4.6 months in cases without muscular symptoms (P < 0.05). No control complained of either muscular pain nor weakness (P < 0.0005). Only one patient (3.3%) had elevated serum creatine phosphokinase concentration (P < 0.0005). We conclude that myopathy is very frequent in patient on both colchicine and cyclosporin. Muscular symptoms improve in all patients after colchicine withdrawal.

Adult↗

PubMed1990

Large-scale purification of bovine brain lactate dehydrogenase by affinity chromatography on immobilized colchicine.

Lactate dehydrogenase (LDH) [EC 1.1.1.27] in a crude extract (40-80% ammonium sulfate fraction) of bovine brain was adsorbed on an immobilized colchicine column and specifically eluted by addition of 1 mM NADH. The purity and subunit composition of the pooled LDH were estimated by two-dimensional gel electrophoresis. With an increase of NaCl concentration from 0 to 2.0 M, ligand saturation of LDH on immobilized colchicine increased from 6.8 to 14%, whereas that on immobilized Cibacron blue F3GA decreased from 2.1 to 0%. In the presence of high NaCl concentration, immobilized colchicine enabled both large- and small-scale purification of LDH by affinity chromatography and resulted in a yield of 117 mg from 1 kg of bovine brain in the presence of 2.5 M NaCl or higher recoveries of 54-96% from various tissues of one rat in the presence of 1.0 M NaCl. These results indicate that immobilized colchicine is an excellent adsorbent for the isolation and purification of LDH by affinity chromatography and has a high LDH-adsorbing capacity dependent upon a high NaCl concentration. Kinetic studies revealed that colchicine apparently competed with cofactor NAD for the active site of LDH and the Ki values of colchicine decreased with an increase of NaCl concentration. The chemical specificity of the colchicine-binding site of LDH was studied by the use of colchicine analogues and it is concluded that both the tropolone moiety (C-ring) and the amido bond in a side chain of colchicine structure are essential to the colchicine-LDH interaction.

Animals↗

PubMed2001

Colchicine toxicity: distinct morphologic findings in gastrointestinal biopsies.

Colchicine is an alkaloid with antimitotic ability used to treat a variety of medical conditions. Colchicine toxicity can result in multiorgan failure and death. The histopathologic features of colchicine toxicity in gastrointestinal biopsies have not been reported. Twenty-one gastrointestinal mucosal biopsies obtained from nine patients receiving oral colchicine therapy were studied. Immunohistochemical staining for Ki67 proliferation antigen was performed, and medical records of each patient were reviewed. All patients had a history of gout. Four patients with chronic renal failure also had clinical evidence of colchicine toxicity, and the other five patients did not. Distinct morphologic changes, seen as metaphase mitoses, epithelial pseudostratification, and loss of polarity, were seen in biopsy material from 4 of 4 (100%) patients with clinical colchicine toxicity. Three of these four cases (75%) also contained abundant crypt apoptotic bodies. These morphologic features were best seen in the biopsies from duodenum and gastric antrum, with relative sparing of the gastric body in the upper gastrointestinal tract. Ki67 staining demonstrated an expansion of the proliferating region in three available cases with clinical colchicine toxicity. These distinctive morphologic features were not seen in the five patients without clinical colchicine toxicity. These results indicate that colchicine toxicity can produce diagnostic morphologic features in gastrointestinal mucosal biopsies. Recognition of these features is important because colchicine toxicity can be fatal if undiagnosed clinically.

Adult↗

PubMed1997

The colchicine-binding and pyrene-excimer-formation activities of tubulin involve a common cysteine residue in the beta subunit.

Colchicine binding and pyrene excimer fluorescence of tubulin have been used to identify cysteine residue(s) essential for the colchicine binding activity of the protein. We report here that both the colchicine binding activity and the ability to form pyrene excimers of tubulin decay at an identical rate when the protein ages at 37 degrees C. Glycerol, which stabilizes the colchicine binding site also stabilizes the excimer formation equally. Thus, these two properties of tubulin are correlated and are likely to belong to the same structural domain. In an attempt to identify the excimer-forming Cys residues, we found that incubation of tubulin with N,N'ethylenebis(iodoacetamide) causes a significant inhibition of excimer fluorescence. Incubation of tubulin with colchicine prior to this treatment fully retains excimer-forming ability. It is known that Cys239 and Cys354 of beta-tubulin, which are about 0.9 nm apart in the native structure, are protected from ethylenebis(iodoacetamide) cross-linking by incubation of tubulin with colchicine [Luduena, R. F. & Roach, M. C. (1981) Pharmacol. Ther. 49, 133-152]. These residues must therefore be responsible for the excimer formation of tubulin with pyrene maleimide. Incubation of tubulin with ethylenebis(iodoacetamide) decreases the colchicine binding activity and the excimer formation at an identical rate. Since the alkylation of Cys239 of beta-tubulin (responsible for tubulin self-assembly) has no effect on colchicine binding [Bai, R., Lin, C. M., Nguyen, N. Y., Liu, T. & Hamel, E. (1989) Biochemistry 28, 5606-5612], our results suggest that excimer formation and the colchicine binding site of tubulin share Cys354 of the beta-subunit. Determination of the number of essential Cys residue(s) for colchicine binding activity, using the statistical method of Tsou [Tsou, C. L. (1962) Sci. Sin. 11, 1535-1558], also shows only one essential Cys residue.

Animals↗

PubMed2004

Effects of colchicine on the maximum biliary excretion of cholephilic compounds in rats.

BACKGROUND AND AIM: Colchicine, an inhibitor of intracellular vesicular transport, has been reported to inhibit the biliary excretion of bile acids and organic anions, but the previous findings are controversial. In order to systematically evaluate the effect of colchicine on the biliary excretion of cholephilic compounds, we studied the effect of colchicine on the biliary excretion of substrates of various canalicular transporters, which were administered at or above the excretory maximum in rats. METHODS: Substrates of various canalicular adenosine triphosphate-binding-cassette transporters were infused at or above the rate of maximum excretion into rats, and the effect of colchicine (0.2 mg/100 g), which was intraperitoneally injected 3 h before, on the biliary excretion was studied. Furthermore, the effect of tauroursodeoxycholate (TUDC) co-infusion on the biliary excretion of taurocholate (TC) after colchicine treatment was also studied. RESULTS: The biliary excretion of TC and cholate administered at the rate of 1 micro mol/min/100 g was markedly inhibited by colchicine, whereas that of TUDC was not inhibited even with the infusion rate of 2 micro mol/min/100 g. TUDC co-infusion at the rate of 1 micro mol/min/100 g increased the biliary excretion of TC (1 micro mol/min/100 g), which was decreased by the colchicine pretreatment. The biliary excretory maximum of taurolithocholate-sulfate and sulfobromophthalein, substrates of the multidrug resistance protein 2, of erythromycin, a substrate of the P-glycoprotein, and of indocyanine green were not affected by colchicine. CONCLUSIONS: The different excretory maximums of TC and TUDC and the different effect of colchicine on the excretion of these bile acids are considered to be a result of different regulatory mechanisms of vesicular targeting of the bile salt export pump to the canalicular membrane by these bile acid conjugates. The vesicular targeting of the multidrug resistance protein 2 and the P-glycoprotein to the canalicular membrane is considered to be colchicine insensitive in the absence of bile acid coadministration.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1996

Modulation of the hepatic alpha 1-adrenoceptor responsiveness by colchicine: dissociation of free cytosolic Ca(2+)-dependent and independent responses.

1. The cytoskeletal depolymerizing agent, colchicine, prevents the hepatic alpha 1-adrenoceptor-mediated stimulation of respiration, H+ and Ca2+ release to the effluent perfusate, intracellular alkalosis, and glycogenolysis. Unlike the other parameters, colchicine does not perturb the alpha 1-agonist-induced stimulation of gluconeogenesis or phosphorylase 'a' activation, and enhances the increase in portal pressure response. The lack of effect of colchicine on the hepatic alpha 2-adrenoceptor-mediated effects indicates that its actions are alpha 1-specific. 2. Colchicine enhances the acute alpha 1-adrenoceptor-mediated intracellular Ca2+ mobilization and prevents the activation of protein kinase C. This differential effect on the two branches of the alpha 1-adrenoceptor signalling pathway is a distinctive feature of the colchicine action. 3. The lack of effect of colchicine in altering the alpha 1-adrenoceptor ligand binding affinity suggests that it might interact with some receptor-coupled regulatory element(s). 4. The acuteness of the colchicine effect and the ability of its isomer beta-lumicolchicine to prevent all the alpha 1-adrenoceptor-mediated responses but the increase in vascular resistance, indicate that its action cannot be merely ascribed to its effects in depolymerizing tubulin. 5. Colchicine perturbs the hepatic responses to vasoactive peptides. It enhances the vasopressin-induced rise of cytosolic free Ca2+ in isolated hepatocytes and prevents the sustained decrease of Ca2+ in the effluent perfusate. It also inhibits the stimulation of glycogenolysis, without altering the stimulation of gluconeogenesis. 6. It is concluded that there are at least two major alpha 1-adrenoceptor signalling pathways. One is colchicine-sensitive, independent of variations in free cytosolic Ca2+, and protein kinase C-dependent; the other one is colchicine-insensitive, dependent on variations in free cytosolic Ca2+, and protein kinase C-independent.

Animals↗