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PubMed1989

A thermodynamic study of the interaction of tubulin with colchicine site ligands.

The bicyclic colchicine analogue 2-methoxy-5-(2',3',4'-trimethoxyphenyl)-2,4,6-cycloheptatrien-1-on e (MTC) has been used to study the thermodynamics of specific ligand binding to the colchicine site of tubulin, employing isothermal reaction microcalorimetry. The binding of MTC to purified calf brain tubulin, in 10 mM sodium phosphate buffer, pH 7.0, is characterized by delta H degree = -19 +/- 1 kJ.mol-1, delta G degree = -31.8 +/- 0.6 kJ.mol-1, and delta S degree = 43 +/- 5 J.mol-1.K-1 at 298 K, with a slight variation in the temperature range from 283 to 308 K. The binding thermodynamics of colchicine and allocolchicine are similar to MTC under the conditions examined, suggesting related molecular interactions of the three ligands with the protein binding site. The standard enthalpy changes of binding of colchicine and MTC at 308 K coincide within experimental error. Therefore the more favorable free energy change of binding of colchicine must come from a larger binding entropy change (by about 20 J.mol-1.K-1). This difference could be attributed to the presence of the middle ring of colchicine, which is absent in MTC. Consistently, a similar entropy change is observed by the comparison of allocolchicine to MTC binding at several temperatures. In addition, allocolchicine binding is about 6 kJ.mol-1 less exothermic than MTC binding, which could be attributed to the presence in allocolchicine of a substituted phenyl ring instead of the colchicine-MTC tropolone ring. The present results and analysis are fully compatible with the previously proposed bifunctional binding of colchicine and MTC (through their trimethoxybenzene and tropolone moieties) to a bifocal protein binding site, and also with a partial immobilization of intramolecular rotation of MTC upon binding, which in colchicine is already constrained by its middle ring (Andreu, J. M., Gorbunoff, M. J., Lee, J. C., and Timasheff, S. (1984) Biochemistry 23, 1742-1752).

Animals↗

PubMed1984

In vitro correction of a deficiency of Con A-induced suppressor cell function in primary biliary cirrhosis by a pharmacological concentration of colchicine.

Patients with primary biliary cirrhosis (PBC) have been previously reported to have immunoregulatory abnormalities. We tested the effect of in vitro colchicine on PBC patients' suppressor cell function in order to determine whether colchicine can correct their suppressor cell deficiency. PBC patients' mononuclear cells were cultured for 44 h with concanavalin A (Con A) as well as with or without colchicine at a pharmacological concentration (10(-8)M) or at a suprapharmacological concentration (10(-5)M) and then tested for their ability to suppress proliferation of phytohaemagglutinin stimulated healthy volunteers' mononuclear cells. Eleven PBC patients had significantly (P less than 0.001) decreased suppressor cell function (12 +/- 15%, mean +/- s.d.) as compared to 37 healthy volunteers (43 +/- 12%). The suprapharmacological concentration of colchicine did not significantly affect the PBC patients' suppressor cell function (16 +/- 15%). In contrast, in the nine PBC patients tested with the pharmacological concentration of colchicine, their suppressor cell function was increased to 40 +/- 20% which was significantly different than without colchicine (P less than 0.01) or with the suprapharmacological concentration of colchicine (P = 0.02) but not significantly different than healthy volunteers. Thus, in vitro colchicine at a pharmacological concentration corrects PBC patients' deficiency of Con A-induced suppressor cell function raising the possibility that oral colchicine might be clinically useful as an immunomodulating drug in PBC.

Aged↗

PubMed1980

Colchicine inhibition of retinol-binding protein secretion by rat liver.

Studies were conducted to explore the effects of colchicine on the secretion and metabolism of retinol-binding protein (RBP) by the liver. In the vitamin A-deficient rat, the rate of secretion of RBP from the liver into the serum is greatly reduced, and RBP accumulates in the liver. Injection of retinol (dispersed in a 20% Tween 40 solution) into deficient rats stimulated a rapid secretion of RBP from the liver into the serum. Colchicine treatment markedly inhibited the retinol-stimulated secretion of RBP from the liver into the serum. The effect of colchicine was most pronounced during the early period after retinol injection, particularly during the first 30 to 60 minutes. Ninety minutes after retinol injection, the serum RBP level of colchicine treated rats was only 36% as great as that of the control rats. In parallel experiments, a quantitatively similar inhibition of very low density lipoprotein (VLDL) secretion by colchicine was observed in the retinol-deficient rats. In contrast, colchicine did not affect the overall rate of hepatic protein synthesis, as estimated from the incorporation of [(3)H]leucine into total liver and serum protein; the secretion of newly synthesized protein was, however, inhibited. When rats were treated with colchicine and then injected with retinol, the level of RBP in a Golgi-rich fraction obtained from the liver homogenate increased markedly as compared to the level of prealbumin. The inhibition of RBP secretion by colchicine suggests that the microtubules play a role in RBP secretion. By analogy to studies on VLDL and albumin, these data provide presumptive evidence that the Golgi apparatus and secretory vesicles are involved in RBP secretion.-Smith, J. E., D. D. Deen, Jr., D. Sklan, and D. S. Goodman. Colchicine inhibition of retinol-binding protein secretion by rat liver.

Animals↗

PubMed1981

Role of B-ring of colchicine in its binding to tubulin.

The chemical specificity of the colchicine-binding site of tubulin is less stringent for the presence of the B-ring than the A- and C-rings of colchicine, Colchicine analogues with modifications in the B-ring bind to tubulin at the same site as colchicine. Analogues with smaller or no substituents in the B-ring bind tubulin remarkably faster than colchicine. Thus, a compound without the B-ring [2-methoxy-5-(2',3',4'-trimethoxyphenyl)tropone] binds tubulin even at 4 degrees C and the binding is almost instantaneous at 37 degrees C. Colcemid and 2-methoxy-5-(2',3',4'-trimethoxyphenyl)tropone bind reversibly to tubulin, whereas colchicine and desacetamidocolchicine bind almost irreversibly, suggesting that the size of the B-ring moiety of colchicine is not related to the reversibility of binding. We conclude that although the presence of the B-ring of colchicine does not appear to be an essential prerequisite for the drug-tubulin interaction, the B-ring substituents play an important role in determining the binding properties of colchicine to tubulin.

Animals↗

PubMed1996

A randomized trial comparing colchicine and ursodeoxycholic acid combination to ursodeoxycholic acid in primary biliary cirrhosis. UDCA-PBC Study Group.

The efficacy of colchicine combined with ursodeoxycholic acid (UDCA) and UDCA alone in the treatment of patients with nonadvanced primary biliary cirrhosis (PBC) was evaluated in a 2-year controlled study. Seventy-four patients with PBC who had been treated previously with UDCA (at least 8 months) but still had abnormal liver test results, especially elevated alkaline phosphatase activity, were randomized to be administered colchicine (1 mg/d, 5 days per week) (n = 37) or a placebo (n = 37). In addition, the patients were treated with UDCA (13-15 mg x kg(-1) x day(-1)). The patients underwent clinical examination and liver tests every 6 months and upper endoscopy and liver biopsy at entry and at 2 years. Procollagen type III aminoterminal peptide (PIIINP), hyaluronic acid, and sulfobromophthalein (BSP) elimination kinetics were determined at entry and after 2 years. After 2 years of treatment, relative to UDCA, colchicine combined with UDCA did not significantly improve symptoms, laboratory findings (serum bilirubin level, alkaline phosphatase and alanine transaminase [ALT] activities, immunoglobulin [Ig] M level), serum markers of fibrosis, or histological features, except lobular inflammation. Colchicine did tend to slightly reduce the progression of esophageal varices; however, the difference was not significant. BSP elimination kinetics (45-minute retention percentage) was significantly improved when treated with colchicine. During the 2-year study, the only clinical complications were variceal bleeding in one patient administered colchicine and two administered the placebo. Two patients died from nonliver causes. One severe adverse effect (peripheral neuromyopathy) was observed in a colchicine-treated patient. In conclusion, this study suggests that colchicine appears to provide a slight advantage relative to UDCA alone in patients with nonadvanced PBC.

Adult↗

PubMed1996

Oral absorption characteristics and pharmacokinetics of colchicine in healthy volunteers after single and multiple doses.

Colchicine is an antimitotic drug used to treat gout and familial Mediterranean fever. Absolute bioavailability, pharmacokinetics, and absorption characteristics of colchicine after single 1.0-mg doses in oral solution or tablet form or 0.5-mg intravenous doses were compared in 6 subjects. This study was combined with 14 days of multiple-dose administration of 1.0-mg colchicine tablets in 6 subjects. Serial blood samples were collected for 48 hours after administration of single doses and for 120 hours after the last dose in the multiple-dose regimen. Plasma colchicine profiles as measured by radioimmunoassay were analyzed using deconvolution and compartmental methods. After intravenous bolus injection of colchicine, the area under the concentration-time curve (AUC) was 61.2 +/- 12.7 ng.hr/mL, steady-state volume of distribution (Vss) was 419 +/- 95 L, systemic clearance (Cl) was 8.5 +/- 1.8 L/hr, and the terminal half-life (t1/2) was 57.8 +/- 10.7 hours. After oral administration in solution form, peak plasma concentrations (Cmax) of 6.50 +/- 1.03 ng/mL were reached at time (tmax) 1.07 +/- 0.55 hours, with a rate of 0.109 +/- 0.024 hr-1 (Cmax/AUC); bioavailability was 47 +/- 14%. Oral tablets yielded similar Cmax, tmax, and Cmax/AUC values, but AUC was significantly lower. Most participants exhibited a secondary peak within 6 hours of administration, possibly in relation to a second absorption site or enterohepatic recirculation. This second absorption process was significantly longer than the first one, and accounted for a similar amount of colchicine absorbed. From the multiple-dose study, a model including an alteration of colchicine absorption due to possible drug-induced gastrointestinal modifications allowed better determination of steady-state plasma concentrations of colchicine.

Absorption↗

PubMed1994

Effect of the nonimmunosuppressive cyclosporin analog SDZ PSC-833 on colchicine and doxorubicin biliary secretion by the rat in vivo.

Colchicine and doxorubicin are secreted into bile as a major pathway of their elimination. Colchicine and doxorubicin are also substrates for P-glycoprotein, and P-glycoprotein has been demonstrated to be present at the liver canalicular membrane. Cyclosporin (CsA) inhibits colchicine biliary secretion in vivo. In the present study, the effects of SDZ PSC-833, a nonimmunosuppressive cyclosporin D analog, on the biliary secretion of colchicine and doxorubicin were investigated. SDZ PSC-833 given at a bolus dose of 2 mg/kg promptly decreased colchicine biliary clearance from 9.05 +/- 0.2 to 2.41 +/- 0.43 ml min-1 kg-1 (P < 0.001) and the colchicine bile/plasma ratio from 146 +/- 8 to 35 +/- 5 (P < 0.001). SDZ PSC-833 also inhibited doxorubicin biliary clearance (basal: 10.5 +/- 3 vs post-SDZ PSC-833: 2.48 +/- 0.94 ml min-1 kg-1; P = 0.06) and the doxorubicin bile/plasma ratio (basal: 228 +/- 64 vs post-SDZ PSC-833: 48 +/- 22; P < 0.01). Colchicine renal secretion was completely inhibited by SDZ PSC-833. Thus, SDZ PSC-833 inhibits the constitutive transport of the multi-drug-resistance substrates colchicine and doxorubicin and is more potent than cyclosporin in this regard. The possibility of increased toxicity to normal tissues because of impaired elimination of cytotoxic agents will need to be considered if SDZ PSC-833 is used to chemosensitize cancer cells.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1985

Stabilization of hepatic colchicine-binding activity by organic acids.

Previous work has shown that the total hepatic tubulin pool and the hepatic microtubule-derived tubulin pool do not have identical [3H]colchicine binding properties. Rapid loss of colchicine-binding activity was noted in the microtubule-derived fractions of liver tubulin. Furthermore, quantitative determination of the total and polymerized tubulin in the liver by the [3H]colchicine-binding assay was hampered by rapid and unequal loss of binding sites under assay conditions. The organic acids, glutamate and glucose 1-phosphate, have been shown to stabilize calf brain tubulin against loss of colchicine-binding sites. Therefore, these compounds were tested as possible protecting agents against loss of colchicine binding activity of liver tubulin. It was found that these agents stabilized liver tubulin under [3H]colchicine-binding conditions. Additional experiments showed that these agents also prevented the rapid loss of colchicine-binding activity that occurred when purified brain tubulin was exposed to liver supernates. These results suggest that the inclusion of the organic acids, glutamate and glucose 1-phosphate, may modify the time decay properties of liver tubulin in solution. Further, these data suggest that these protecting agents may be of analytical value in [3H]colchicine-binding assay systems for liver tubulin.

Animals↗

PubMed1986

The effect of colchicine on cholesterol processing by the progesterone-producing cells of the luteinized ovary.

Previously, we indicated that luteal cells from colchicine-treated superovulatory (luteinized) rats show decreased capacity for progesterone production. The current study investigates the possibility that colchicine exerts this effect by interfering with the mechanism by which cholesterol is processed and/or synthesized by luteal cells. To this end, animals were treated with saline or colchicine after which the luteinized ovary or isolated luteal cells were assayed for their cholesterol content, their ability to synthesize cholesterol endogenously, or their ability to utilize lipoprotein-delivered cholesterol for the production of progesterone. The results show that animals treated with colchicine show a number of changes in luteal cell cholesterol metabolism: namely a 60% decline in stored cholesterol, a 3-fold rise in the activity of the cholesterol synthesizing enzyme HMG CoA reductase (although no change occurs in other cholesterol metabolizing enzymes), and a 3-fold rise in the capacity of the cells to incorporate precursor [14C]acetate into cholesterol. On the other hand, cells of animals treated with colchicine or cells treated with colchicine under in vitro circumstances are unable to fully utilize cholesterol provided by high density lipoproteins (HDL): this occurs despite the fact that the binding of HDL particles to luteal cells is quite normal after colchicine treatment. These findings are consistent with the view that a primary effect of colchicine on luteal cell progesterone production is in preventing the normal uptake of HDL-cholesterol.

Animals↗

PubMed1984

Neurotoxicity of colchicine and other tubulin-binding agents: a selective vulnerability of certain neurons to the disruption of microtubules.

Colchicine and certain other agents which disrupt microtubules and interfere with axonal and dendritic transport are highly toxic to certain CNS neurons. The present chapter summarizes our knowledge about this selective neurotoxicity. Injections of colchicine into several bran regions lead to the death of selected populations of neurons within those regions. Intra-hippocampal injections selectively destroy granule cells of the dentate gyrus; hippocampal pyramidal cells are essentially unaffected. Injections into the cerebellum, olfactory bulb, and caudate nucleus also destroy resident neurons. In these areas several cell types are vulnerable. Neurons of the cerebral cortex appear to be much less affected by colchicine, although some neurons of paleocortical regions are vulnerable. Colchicine does not appear to be an excitotoxin like kainic acid. The neurotoxicity of colchicine appears to be related to the destruction of microtubules, since other agents which disrupt microtubules have similar toxic effects, and since analogs of colchicine which do not disrupt microtubules are non-toxic. Colchicine may induce an autotoxic response which leads to neuronal death in certain populations due to the accumulation of some toxic cellular product which is normally transported by a microtubule-dependent process. The selective vulnerability of neurons to the neurotoxic effects of colchicine may be a model for system degenerations of the central nervous system in which certain subpopulations of neurons are selectively vulnerable to abnormal accumulations of metabolic products.

Animals↗

PubMed1991

Colchicine intoxication: clinical pharmacology, risk factors, features, and management.

The use of colchicine for acute gouty arthritis dates to ancient times. In recent years, colchicine also has been used successfully for various other rheumatic and nonrheumatic conditions. Colchicine is a safe drug when used according to established therapeutic guidelines. However, toxicity can be considerable if ingested intentionally or if the recommended doses are exceeded. Colchicine intoxication is characterized by multi-organ involvement and by the poor prognosis associated with administration of large amounts of the drug. Therapy is basically supportive and symptomatic because of the rapid distribution and binding of colchicine to the affected tissues. Use of anticolchicine antibodies is a novel approach that has shown promise in experimental models. Important research questions pertain to the effect of liver and kidney disease on colchicine metabolism, use of colchicine levels in the diagnosis of intoxication and for prognostication, and application of immunotoxicotherapy for colchicine poisoning in humans.

Animals↗

PubMed1975

Characterization of a colchicine receptor protein in rat epididymal adipose tissue.

Colchincine was found to be taken up by adipose tissue and therein to bind to a soluble macromolecule not sedimented by centrifugation for 2 h at 100 000 x g. A similar binding occurred when soluble extracts of adipose tissue were incubated with colchicine. The binding reaction reaction is temperature dependent and shows a pH optimum between 6.8 and 7.0. Double reciprocal plots of colchicine concentration versus amounts of colchicine bound to protein in the steady state disclosed an apparent Km of 0.250 to 1.5 muM. The colchicine binding activity of soluble tissue extracts decreased when the extracts were incubated at 37 degree C. Addition of guanosine triphosphate and Mg-2+ retarded the loss of colchicine binding activity. The molecular weight of the colchicine complex was estimated to be 115 000 and its sedimentation coefficient 5.8 S. All of these characteristics are remarkably similar to those of the protein tubulin which has been isolated from other tissues. Since it is now well known that tubulin is a protein subunit of cytoplasmic microtubules, it is suggested that the previously reported metabolic effects of colchicine on adipose tissue result from the dissolution of microtubules by colchicine.

Adipose Tissue↗

PubMed1989

Intrahippocampal colchicine injection results in spectrin proteolysis.

Neurons in the hippocampal formation vary markedly in their susceptibility to colchicine toxicity. The present study was directed at evaluating the effects of colchicine on the proteolytic breakdown of the cytoskeletal protein spectrin within the hippocampus in the rat. Quantified by immunoblot analysis of spectrin breakdown products, the extent of proteolysis was found to correlate with the relative vulnerability of different hippocampal subfields to colchicine toxicity. Levels of breakdown products increased dramatically between 1 and 2 days after colchicine injection, peaked between 2 and 4 days, and remained detectably elevated for at least 35 days. Two days after colchicine injection, the spectrin breakdown products were significantly more concentrated in the molecular layer than in the granule cell/hilar region of the dentate gyrus. The colchicine-induced increase in spectrin breakdown products was significantly reduced by pretreatment with the protease inhibitor leupeptin and was significantly elevated by pretreatment with the lysosomal inhibitor chloroquine. Immunohistochemical analyses of the hippocampus at various times after colchicine injection revealed changes in the distribution of spectrin-like immunoreactivity that paralleled the changes observed by Western blot analysis. Thus increased staining was observed in the molecular layer of the dentate gyrus at 2 and 4 days after the injection, while staining in CA3 was only slightly increased. In addition, abnormal staining of reactive astrocytes was prominent at 2 days. The mechanism whereby colchicine results in neuronal death is as yet unknown. However, the results presented here demonstrate that extensive proteolysis of a cytoskeletal protein occurs in response to the drug, suggesting a plausible mechanism for its neurotoxicity. The protease responsible for the effect is likely to be calpain since the process is non-lysosomal, leupeptin-sensitive and produces spectrin breakdown products indistinguishable from those generated by calpain treatment in vitro. These data support the hypothesis that calpain-mediated degradation of cytoskeletal elements is a common and early response to neurodegenerative events and serves as a trigger in the development of various neuropathologies.

Animals↗

PubMed1992

Ineffectiveness of colchicine for the prevention of restenosis after coronary angioplasty.

Colchicine, an antimitogenic agent, has shown promise in preventing restenosis after coronary angioplasty in experimental animal models. A prospective trial was conducted involving 197 patients randomized in a 2:1 fashion to treatment with oral colchicine, 0.6 mg twice daily (130 patients), or placebo (67 patients) for 6 months after elective coronary angioplasty. Treatment in all patients began between 12 h before angioplasty and 24 h after angioplasty. Compliance monitoring revealed that 96% of all prescribed pills were ingested. Demographic characteristics were similar in colchicine- and placebo-treated groups. A mean of 2.7 lesions/patient were dilated. Side effects resulted in a 6.9% dropout rate in the colchicine-treated patients. Complete quantitative angiographic follow-up was obtained in 145 patients (74%) with 393 dilated lesions. Quantitative angiographic measurements were obtained in two orthogonal views at baseline before angioplasty and immediately and at 6 months after angioplasty. The quantitative mean lumen diameter stenosis before angioplasty was 67% both in the 152 lesions in the placebo-treated group and in the 241 lesions in the colchicine-treated group; this value was reduced to 24% immediately after angioplasty in the lesions in both treatment groups. At the 6-month angiogram, lesions had restenosed to 47% lumen diameter narrowing in the placebo-treated group compared with 46% in the colchicine-treated group (p = NS). Forty-one percent of colchicine-treated patients developed restenosis in at least one lesion compared with 45% of the placebo-treated group (p = NS). In conclusion, colchicine was ineffective for preventing restenosis after coronary angioplasty.

Angioplasty, Balloon, Coronary↗

PubMed2003

Colchicine induces membrane-associated activation of matrix metalloproteinase-2 in osteosarcoma cells in an S100A4-independent manner.

Like the metastasis-associated protein S100A4, matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) are important in physiological and pathological conditions. Previously, we showed that S100A4 is involved in the regulation of MMPs and TIMPs, and in the present work we have investigated whether the anti-inflammatory and microtubule-disrupting drug colchicine has an effect on the expression of these proteins in osteosarcoma cell lines (OHS) with high and low levels of S100A4. Colchicine treatment of the various OHS cells resulted in an increased expression of MT1-MMP and TIMP-2 mRNA, and a corresponding increase of these two proteins in isolated cell membranes. Colchicine-treated cells produced more of the activated form of MMP-2 than control cells. However, the drug did not affect the amount of MMP-2 and TIMP-1 mRNA or protein, and it reduced the S100A4 mRNA expression. Isolated cell membranes from the colchicine-treated cells were more effective in activating exogenous proMMP-2 than membranes from control cells, and inhibitory studies indicated that it was the colchicine-induced increase in MT1-MMP that caused the increased activation of endogenous MMP-2. A peptide inhibitor of nuclear factor kappaB nuclear translocation, SN50, blocked the colchicine-induced activation of proMMP-2 and reduced the synthesis of MMP-2 in colchicine-treated cells, but not in control cells. It can be concluded that colchicine modulates the expression of MT1-MMP and TIMP-2 and hence the activation of proMMP-2 independently of the S100A4 level in osteosarcoma cells.

Cell Membrane↗

PubMed2004

Increased chloride efflux in colchicine-resistant airway epithelial cell lines.

Colchicine has been proposed as a treatment to alleviate chronic lung inflammation in cystic fibrosis patients and clinical trials are ongoing. Our aim was to investigate whether chronic exposure of cystic fibrosis cells to colchicine can affect their ability to transport chloride in response to cAMP. Colchicine-resistant cells were selected by growing in medium containing nanomolar concentrations of the drug. While microtubuli were affected by acute exposure to colchicine, they appeared normal in colchicine-resistant cells. Colchicine-resistant clones had higher expression of multidrug resistance proteins compared to untreated cells. Cystic fibrosis transmembrane conductance regulator (CFTR) labelling by immunocytochemistry showed no significant changes. The intracellular chloride concentration and basal chloride efflux of the cystic fibrosis treated cells increased significantly compared with untreated cells, while for the cAMP-stimulated Cl-efflux there was no significant change. The results suggest that colchicine promotes chloride efflux via alternative chloride channels. Since this is an accepted strategy for pharmacological treatment of cystic fibrosis, the results strengthen the notion that colchicine would be beneficial to these patients.

Biological Transport↗

PubMed2003

Exocytotic "constipation" is a mechanism of tubulin/lysosomal interaction in colchicine myopathy.

Colchicine, a known microtubule disrupting agent, produces a human myopathy, characterized by accumulation of lysosomes. We have created a reliable animal model of colchicine myopathy that replicates the subacute myopathy seen in humans, reproducing the chronic proximal weakness and vacuolar changes in nonnecrotic myofibers. If a microtubule network plays a role in lysosomal function in muscle, disturbance of it could alter degradation of intrinsic membrane receptors, presumably at some intracellular processing site or at exocytosis. Thus, we examined, as a possible cellular pathogenesis of colchicine myopathy, how the muscle cytoskeleton affects the degradation of membrane proteins, which are processed through the endosomal/lysosomal pathway. We used the acetylcholine receptor as a model membrane component in cultured myotubes allowed to preincubate with colchicine. We tested at which step colchicine interferes with receptor trafficking by accounting for internalization, delivery to lysosomes, hydrolysis, or exocytotic release of debris. We report that colchicine significantly decreases the exocytosis of AChRs but does not affect receptor internalization, lysosomal hydrolysis, or the number of surface membrane receptors. Further, our immunofluorescence observations revealed a morphologic tubulin network in rat skeletal muscle that is more densely distributed in white (mitochondria-poor) muscle fibers than in red (mitochondria-rich) fibers but is present in both. Ultrastructurally, immunogold labeling localized tubulin in the intermyofibrillar region in a long and linear fashion, unassociated with myofibers or mitochondria. Taken together, our findings suggest the following: (1) Microtubules likely play a functional role in the pathway of lysosomal degradation in normal adult skeletal muscle; (2) The observed decrease in overall apparent degradation of membrane receptors by colchicine must be due primarily to inhibition of exocytosis. These data indicate that lysosomal "constipation" underlies colchicine myopathy. (3) An animal model faithful to the human disorder will allow further pathogenetic studies.

Animals↗

PubMed1997

Dual action of colchicine on hypertonic activation of system A amino acid transport in vascular smooth muscle cells.

Amino acid transport system A is present in many cells and tissues and is regulated by hormones and other factors, including hypertonic stress. System A in vascular smooth muscle cells is also activated when microtubules are disrupted by drugs such as colchicine. The present study examined the action of colchicine on hypertonic activation of system A in smooth muscle cells. In serum-free medium, activation of system A by modest (340 mOsm) hypertonicity was not affected by colchicine addition. However, at high osmotic stress (460 mOsm) the addition of colchicine partially blocked the activation of system A. Addition of colchicine alone, at normal osmolarity, produced activation of system A. In the presence of serum, colchicine action was markedly different. Colchicine consistently inhibited hypertonic activation of system A at any degree of hypertonic stress but had no effect on system A at normal osmolarity. The action of colchicine as both an activator and inhibitor of system A implies microtubule involvement at more than one step in the intracellular regulation of system A.

Amino Acids↗