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PubMed1984

Ultrastructural study of colchicine neurotoxicity in septohabenulointerpeduncular system.

Colchicine is selectively neurotoxic towards some neuronal populations and causes the death of sensitive neurons. Electron microscopic examination of the neural damage caused by stereotaxic injections of colchicine has been used to demonstrate neuroanatomical connections in the septohabenulointerpeduncular system of the rat brain. Colchicine injections in the medial habenula were selectively neurotoxic towards some neurons of the medial habenula and resulted in degeneration of S and crest terminals, the most common type of interpeduncular synapses. Control injections in the stria medullaris, rostral to the habenular complex, caused only sparse degeneration in the interpeduncular nucleus and did not involve S and crest terminals. Colchicine injections that caused neuronal degeneration in the supracommissural septum resulted in substantial terminal degeneration in the interpeduncular nucleus. A large number of degenerated terminals was also present, in these cases, in the medial habenula. Colchicine administration in the various areas caused, to a different extent, lesion or minor ultrastructural damage to axons crossing the injected area. The potential usefulness of colchicine neurotoxicity for neuroanatomical purposes is discussed and the limitation derived from damage of fibers of passage is considered. Colchicine can be confidently used in experimental studies only when erroneous interpretation caused by damage of fibers of passage can be excluded. In the present investigation, this prerequisite could be achieved either by controls made possible by the peculiar arrangement of neuronal circuits or by comparison with known anatomical data.

Animals↗

PubMed1993

Effect of colchicine on lactate production by isolated hepatocytes in rats treated with carbon tetrachloride and ethanol.

This study was designed to evaluate the lactate production by isolated hepatocytes in rats with cirrhosis induced by means CCl4 + ethanol and the effect of colchicine in this experimental model of fibrosis. The effect of colchicine on lactate metabolism may be important in explaining the beneficial mechanism of this therapy on liver cirrhosis. Colchicine treatment produced a decrease in perivenular fibrosis and a descense in the degrees of this histological lesion. Colchicine treatment ameliorated the subsequent further development of cirrhosis. Lactate production in colchicine groups were higher than the carbon tetrachloride groups. By contrast, a priori, we observed a decrease in lactacidaemia and a lesser lactate utilization in colchicine groups comparison with CCl4 + ethanol groups. Our results suggest that colchicine improves the fibrosis by a mechanism independent of hepatic lactate metabolism.

Animals↗

PubMed2005

Electrochemistry and voltammetric determination of colchicine using an acetylene black-dihexadecyl hydrogen phosphate composite film modified glassy carbon electrode.

The electrochemical behavior of colchicine at an acetylene black-dihexadecyl hydrogen phosphate (denoted as AB-DHP) composite film coated glassy carbon electrode (GCE) was investigated using cyclic voltammetry (CV), linear sweep voltammetry (LSV) and differential pulse voltammetry (DPV). Compared with the poor electrochemical signal at the unmodified GCE, the electrochemical response of colchicine at the AB-DHP film modified GCE was greatly improved, as confirmed from the significant peak current enhancement. The remarkable peak current enhancement indicates that the AB-DHP modified GCE has great potential in the sensitive determination of colchicine. Thus, all the experimental conditions, which influence the electrochemical response of colchicine, were studied and the optimum conditions were achieved. Finally, a sensitive and simple voltammetric method with a good linear relationship in the range of 1.0 x 10(-7) approximately 4.0 x 10(-5) mol/L, was developed for the determination of colchicine. The detection limit of colchicine was also examined and a low value of 4.0 x 10(-8) mol/L for 4-min accumulation was obtained (S/N=3). This electrode was successfully applied to detect colchicine in human urine samples.

Acetylene↗

PubMed2005

99mTc-labeling of colchicine using [99mTc(CO)3(H2O)3]+ and [99mTc triple bond N]2+ core for the preparation of potential tumor-targeting agents.

Multidrug resistance (MDR) mediated by over-expression of P-glycoprotein (Pgp) is one of the major causes of failure of chemotherapy in cancer treatment. Colchicine, a naturally occurring alkaloid, is a Pgp substrate and acts as an antimitotic agent by binding to microtubules. Hence, Colchicine and its analogues radiolabeled with 99mTc may have potential for visualization of MDR in tumors. Here we report 99mTc-labeling of colchicine derivatives using [99mTc(CO)3(H2O)3]+ and [99mTc triple bond N]2+ cores. Trimethylcolchicinic acid synthesized from colchicine was used as the precursor to prepare iminodiacetic acid and dithiocarbamate derivatives which were then radiolabeled with [99mTc(CO)3(H2O)3]+ and [99mTc triple bond N]2+ cores, respectively. Radiolabeling yield for both the complexes was > 98% as observed by HPLC and TLC patterns. In vitro studies in tumor cell lines showed significant uptake for 99mTc-carbonyl as well as for 99mTc-nitrido colchicine complexes. Biodistribution studies in Swiss mice bearing fibrosarcoma tumor showed 4.1 +/- 1.2% ID/g of uptake at 30 min pi for 99mTc(CO)3-complex as against 0.42 +/- 0.24% ID/g for the 99mTcN-complex. 99mTc(CO)3-colchicine complex exhibited better pharmacokinetics with lower liver accumulation as compared to the 99mTcN-complex. Thus, colchicine radiolabeled with [99mTc(CO)3(H2O)3]+ core is more promising with respect to in vivo distribution characteristics in tumor model.

Animals↗

PubMed2006

Differential effects of cyclooxygenase inhibitors on intracerebroventricular colchicine-induced dysfunction and oxidative stress in rats.

Alzheimer's disease is a progressive neurological and psychiatric disorder. Oxidative stress and neuroinflammation have been implicated in pathophysiology of Alzheimer's disease. Inflammatory cells, such as astrocytes and microglia, are activated in areas of the brain affected by amyloid plaques and inflammatory mediators including cytokines, chemokines, prostaglandins, oxygen free radicals and reactive nitrogen species may have a crucial role in Alzheimer's disease pathogenesis. Central administration of colchicine, a microtubule-disrupting agent, causes loss of cholinergic neurons and cognitive dysfunction that is associated with excessive free radical generation. The present study was aimed to evaluate the effects of cyclooxygenase inhibitors against colchicine-induced cognitive dysfunction and oxidative stress in rats. Following intracerebroventricular (i.c.v.) administration of colchicine (15 microg/5 microl), rats exhibited poor retention of memory in Morris water maze and elevated plus maze task paradigms and oxidative stress in rats. Chronic treatment with naproxen (per se; 20 and 40 mg/kg, p.o.) or valdecoxib (per se; 5 and 10 mg/kg, p.o.) daily respectively for a period of 25 days beginning 4 days prior to colchicine injection significantly improved colchicine-induced cognitive impairment. Intracerebroventricular colchicine injection resulted in free radical generation characterized by alterations in oxidative stress markers with a significant increase in malondialdehyde and nitrite levels and depletion of reduced glutathione levels in the brains of rats. It also caused a decrease in acetylcholinesterase activity. Besides, improving cognitive dysfunction, chronic administration of cyclooxygenase inhibitors (naproxen and valdecoxib) significantly reduced elevated malondialdehyde, nitrite levels and restored reduced glutathione levels and acetylcholinesterase activity. The results of the present study indicated that naproxen (per se; 20 and 40 mg/kg, p.o.) or valdecoxib (per se; 5 and 10 mg/kg, p.o.) treatment has a neuroprotective role against colchicine-induced cognitive impairment and associated oxidative stress. The present findings further support the potential use of cyclooxygenase inhibitors in treatment of neurodegenerative diseases such as Alzheimer's disease.

Acetylcholinesterase↗

PubMed2004

Colchicine poisoning: case report of two suicides.

Colchicine overdose is uncommon but potentially life threatening because of the high toxicity of the drug. Poisoning by colchicine may occur following ingestion of medication used in acute attacks of gout and inflammatory diseases. We describe two cases involving suicide by the ingestion of medications marketed in France. In case 1, only heart blood was taken after body external examination. In case 2 an autopsy was performed and heart blood, urine, gastric contents and bile were taken for toxicological analysis. Colchicine was assayed in biological specimens by an HPLC-DAD method, after extraction by dichloromethane at pH 8, adding prazepam as internal standard (IS). Analyses were performed on a Symetry C-8 column. Mobile phase was a gradient of acetonitrile/pH 3.8 phosphate buffer. Colchicine is eluted at 13.1 min and the method is linear for blood, urine and bile over the range 4-1000 ng/mL. LOQ is 4 ng/mL. The concentrations of colchicine detected are: case 1: heart blood 13 ng/mL; case 2: heart blood 66 ng/mL, urine 500 ng/mL, gastric content 12 ng/mL, bile 5632 ng/mL. Our findings are in the range of lethal concentrations previously described, but there is no correlation with the amount of ingested drug. Even after massive overdose, it could be impossible to detect colchicine in blood, and as there is a widespread enterohepatic recirculation before excretion in bile and feces, bile is the target sample to analyse. We conclude in both cases that the cause of death was suicide with colchicine. It appears very important to perform an autopsy in order to obtain bile, urine, heart blood and femoral blood.

Adult↗

PubMed2001

Colchicine-induced cytoskeletal collapse and apoptosis in N-18 neuroblastoma cultures is rapidly reversed by applied S-100beta.

Brain connections depend on a stable association between dendrites and axons whose cytoskeleton is stabilized by the proteins MAP-2 and tau, respectively. The glial protein S-100beta inhibits the phosphorylation by PKC of these two microtubule-associated proteins. In order to determine if exogenous S-100beta can directly influence the cytoskeleton of living cells, cultures of N-18 cells (neuroblastoma clonal cell line) are treated for 30 min in serum-free medium with 10(-6) M colchicine. In normal media, colchicine induces a rapid retraction of processes, membrane blebbing, nuclear collapse, and cell death. The observed cellular changes, due to cytoskeletal collapse after exposure to colchicine, are similar and consistent with the loss of processes and cytoplasmic blebbing seen in cells undergoing apoptosis. The addition of 20 ng/ml of S-100beta after the initial 30-min exposure to colchicine prevents apoptosis, nuclear collapse and induces the regrowth of retracted processes. Cells were treated with the Hoechst Stain, a fluorescent marker that binds to nuclear material, to determine the occurrence of apoptosis in our cultures. In our control cultures, receiving no drugs, we found that 15.1% of the cells were apoptotic. When colchicine was added to the culture medium we found that 31.6% of the cells became apoptotic. However, when colchicine was followed by exposure to S-100beta we found that only 5.4% of the cells were apoptotic. Our results suggest that extracellular application of the glial protein S-100beta is sufficient to reverse colchicine-induced cytoskeletal collapse and prevent the resultant apoptosis of the cells. The increased levels of S-100beta seen after brain injury and in certain neurological and psychiatric disorders may be considered as beneficial for brain recovery.

Apoptosis↗

PubMed1997

Interindividual variation in cytogenetic response to X-ray and colchicine measured with the cytokinesis-block micronucleus assay.

Interindividual variation in cytogenetic response to two different types of micronucleus (MN) inducer, X-rays (a clastogen) and colchicine (a spindle poison), was investigated in the peripheral blood lymphocytes of normal healthy donors by the cytokinesis-block MN method. The data for 124 donors between the ages of 19 and 80 years showed that the histogram of individual frequency of X-ray (2 Gy)-induced micronucleated cells followed the normal distribution (Shapiro Wilks W-test) with a significant interindividual variance (ANOVA, p < 0.001). This was, however, not the case for colchicine (0.03 microgram/ml)-induced micronucleated cells. Instead, a skewed distribution illustrating interindividual variation was evident (ANOVA, p < 0.001). Statistical analysis of the effect of age and sex on MN incidence by using the Kruskal-Wallis test indicated that age affected the baseline and colchicine-induced MN incidences strongly but not the X-ray-induced MN incidence. There was no effect of sex on the incidence of micronuclei induced by either agent. In order to avoid any possible effect of age on the MN index, data for young subjects aged less than 30 years old were analyzed separately. The results of this analysis again showed significant interindividual variations in baseline, X-ray-induced, and colchicine-induced micronucleated cell rates. Results of the correlation-coefficient analysis showed that neither X-ray-induced MN incidence nor colchicine-induced MN incidence was related to baseline MN incidence. No correlation between X-ray-induced and colchicine-induced MN incidences was also found by this analysis. These results suggest that interindividual variance in chromosomal response to mutagens in normal populations may be a real phenomenon, as is interindividual variance in baseline MN frequency, and that individual susceptibilities to the two different types of micronucleus inducers (X-ray and colchicine) are unrelated, and the baseline MN level is not of predictive value for the susceptibilities.

Adult↗

PubMed1993

Colchicine in the treatment of AA and AL amyloidosis.

Colchicine is an effective medication in the prevention and treatment of amyloidosis of familial Mediterranean fever. Its therapeutic effect depends on the stage of renal disease and the drug dose. To evaluate colchicine effect in AA amyloidosis of other diseases and in primary AL amyloidosis, the literature was reviewed. Findings were that (1) the effect of colchicine in reactive amyloidosis has not been methodically studied, but anecdotal reports suggest it may be beneficial; and (2) the results of studies and case reports on the effect of colchicine in primary amyloidosis are conflicting. Because a therapeutic effect of colchicine in primary and reactive amyloidosis has been shown in sporadic cases, a prospective, controlled, multicenter study assessing the effect of colchicine in all types of amyloidosis appears to be justified. Until such a study is available, the addition of colchicine in an appropriate dose to any therapeutic regimen of patients with AA or AL amyloidosis should be considered.

Adult↗

PubMedDate not supplied

Involvement of microtubule integrity in memory impairment caused by colchicine.

In order to fully evaluate the effects of colchicine treatment on learning ability in rats, colchicine was administered, and both Morris water maze (MWM) and step-through type passive avoidance (PA) learning tests were conducted. In both learning tests, infusion of colchicine into the rat dentate gyrus, at two distinct bilateral rostrocaudal locations, potently impaired memory function in a dose-dependent manner (0.01-2.0 microg/site), whereas systemic injection of colchicine (50-300 microg/kg) did not. In the MWM test, memory impairment was observed even at doses where there was no evidence of any histological changes in the dentate granule cells. This suggests that functional deterioration, that is, learning impairment was induced by the dysfunction of microtubules and/or axons, was caused by colchicine. Moreover, ameliorated learning behavior was observed with chronic treatment of beta-estradiol 3-benzoate, which has been suggested to have an important role as an adjuvant treatment for younger Alzheimer's disease (AD), immediately after colchicine infusion (0.3 microg). These results indicate that the animal model accompanying the colchicine-induced functional defect showing early tau pathology, but not neuronal cell degeneration, may well mimic comparatively early stage of AD.

Alzheimer Disease↗

PubMedDate not supplied

Colchicine inhibits human trophoblast differentiation in vitro.

When cultured in keratinocyte growth medium, mononuclear cytotrophoblast cells aggregate into multicellular colonies which then fuse to form multinucleated syncytiotrophoblast. In an attempt to characterize better the mechanism of human trophoblast differentiation and to obtain information about the role of the cytoskeleton, experiments were performed using cytoskeletal-disrupting drugs and primary cultures of cytotrophoblast cells from term placentae. Addition of colchicine 6 h after plating permitted aggregation but the cells did not form syncytiotrophoblast, as revealed by staining for desmosomes and nuclei. Staining with an anti-tubulin antibody showed that microtubules were present in untreated control cells but absent in colchicine-treated cultures. If colchicine was added 24 h after plating, the cells also failed to differentiate. When cells were exposed to colchicine for the first 24 h after plating and then cultured in the absence of the drug, differentiation proceeded normally. Cells exposed to colchicine for 48 h and then incubated in the absence of the drug failed to form syncytiotrophoblast. The results suggest that a decision to differentiate is made between 24 and 48 h after plating. The effects of colchicine were observed between 2.5 and 250 microM. Beta-lumicolchicine blocked differentiation at 250 microM but was ineffective at lower concentrations. Colchicine also inhibited HCG secretion in a dose-dependent manner; beta-lumicolchicine only caused inhibition at 250 microM. Staining with antitubulin antibody revealed that lumicolchicine-treated cells had intact microtubules. These results suggest a role for microtubules in trophoblast differentiation.

Actin Cytoskeleton↗

PubMed1989

Colchicine-induced alterations of reference memory in rats: role of spatial versus non-spatial task components.

Male, Fischer-344 rats received bilateral injections of 2.5 micrograms of colchicine per site in the dorsal and ventral hippocampus. Intradentate colchicine preferentially destroyed dentate granule cells. Subsequent behavioral studies showed that 3 weeks after dosing, colchicine impaired the acquisition of a spatial, reference memory task in the Morris water maze. In a second group of rats, which were trained in the water maze prior to dosing, intradentate colchicine impaired retention of this task when rats were tested 3 weeks later. The acquisition of non-spatial reference memory task, an autoshape of a lever touch response in an operant chamber, was facilitated by prior administration of colchicine. Facilitative effects of colchicine were seen if delays of 0, 4, or 6 s were interposed between response and presentation of food reinforcement. If rats were trained to lever-touch with either a 0- or 4-s delay between response and reinforcement, intradentate colchicine had no effect on retention of the response 3 weeks later. These data are in accord with the conclusion that the dentate gyrus plays an important role in the acquisition of new information and retrieval of previously learned material and is an integral neural substrate for reference memory involving a spatial component.

Animals↗

PubMed1993

Early colchicine administration reduces hepatic fibrosis and portal hypertension in rats with bile duct ligation.

Chronic administration of colchicine has been suggested as a potential treatment for hepatic fibrosis. The purpose of this study was to examine the effects of chronic oral administration of colchicine on the histological and hemodynamic abnormalities of bile duct ligation in the rat. Forty-eight rats with ligation-section of the common bile duct were randomly and blindly assigned to receive either colchicine (50 mu/kg day) or placebo by gavage for 4 weeks. At the end of the treatment period, morphometric analysis showed that hepatocyte and sinusoidal volume fractions were significantly higher in rats treated with colchicine than in rats receiving placebo (42.4 +/- 1.3 vs. 32.1 +/- 2.6% (mean +/- S.E.) and 8.3 +/- 0.6 vs 4.7 +/- 0.4%, respectively), while bile duct volume fractions (reflecting bile ductular proliferation) and connective tissue fractions were significantly lower in rats treated with colchicine than in rats receiving placebo (12.1 +/- 0.9 vs. 17.0 +/- 0.1% and 37.2 +/- 0.9 vs. 46.1 +/- 2.0%, respectively). Portal pressure (13.4 +/- 0.7 vs. 17.8 +/- 0.5 mmHg), portal tributary blood flow (5.8 +/- 0.4 vs. 8.7 +/- 0.5 ml.min-1.100 g-1) and cardiac index (40.8 +/- 2.3 vs. 50.6 +/- 1.5 ml.min-1.100 g-1) were significantly lower in colchicine-treated rats than in placebo treated animals. In conclusion, in rats with bile duct ligation, colchicine limits the severity of liver lesions and, consequently, of portal hypertension and hyperkinetic syndrome.

Administration, Oral↗

PubMed1999

Biphasic effect of colchicine on acute liver injury induced by carbon tetrachloride or by dimethylnitrosamine in mice.

BACKGROUND/AIMS: The effects of colchicine on acute liver injury induced by carbon tetrachloride or by dimethylnitrosamine in mice were examined. METHODS: Nonlethal acute liver injury was induced in male BALB/c mice by a single intraperitoneal injection of 0.8 ml/kg carbon tetrachloride or 15 mg/kg dimethylnitrosamine. 0.6 mg/kg colchicine was administered 18 h or 2 h intraperitoneally before hepatotoxin treatment. RESULTS: Reversible centrilobular to mid-zone necrosis and apoptosis occupying half the liver lobular area was evoked by carbon tetrachloride, and dimethylnitrosamine, respectively. Administration of colchicine 18 h before hepatotoxins markedly suppressed liver injury, whereas colchicine administration 2 h before the hepatotoxins accelerated it. The hepatoprotective effect evoked by colchicine was due to reduction in liver cytochrome P450 content and P450 2E1 activity. In contrast, the hepatodestructive effect seen in the carbon tetrachloride model was related to the extent of lipid peroxidation promoting plasma membrane destruction, while the hepatodestructive effect in the dimethylnitrosamine model was due to suppression of Bcl-X(L) expression, leading to acceleration of apoptosis. CONCLUSIONS: A biphasic effect of colchicine on carbon tetrachloride- and dimethylnitrosamine-induced acute liver injury was seen. The time interval between colchicine administration and the hepatotoxin treatment is crucial to the subsequent development of liver lesions.

Alanine Transaminase↗

PubMed1987

Colchicine does not provide a sustained blockage of collagen and plasma protein secretion by rat hepatocytes.

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

Animals↗

PubMed1999

The effect of perineural colchicine on nerve injury-induced spinal glial activation and neuropathic pain behavior.

Factors transported centrally from the site of a peripheral nerve injury are known to provide cellular activation signals to the dorsal root ganglion and spinal cord. Yamamoto and Yaksh [35] were able to use colchicine disruption of axonal transport to abolish thermal hyperalgesia after sciatic chronic constriction in the rat. The current study set out to ascertain whether this observation could be reproduced by applying the same pharmacologic paradigm to a complete, segmentally specific, spinal nerve tight ligation (SPTL) and assessing the impact of this treatment on mechanical allodynia and central, spinal glial activation. Mechanical allodynia of the ipsilateral (lesion side) hind paw was measured at 1, 3, 5, 7, 10, and 14 days following SPTL. Spinal astrocytic and microglial activation were assessed immunohistochemically at 5 and 14 days. Colchicine was unable to prevent mechanical allodynia or spinal glial activation when applied perineurally just proximal to the site of SPTL. Administered alone, colchicine (without SPTL) induced both astrocytic and microglial activation, but not mechanical allodynia. Colchicine applied distal to the site of SPTL did not alter mechanical allodynia or glial responses to SPTL. Neuronal tracing experiments were performed to verify segmental disruption of axonal transport by either SPTL or colchicine treatment. Neuronal tracer injected into the sciatic nerve could not be found at the L5 spinal level following perineural colchicine treatment or tight ligation of the L5 spinal nerve, however, tracer was present at the unobstructed L4 spinal level. These results suggest that central astrocytic and microglial responses may be triggered by disruption of transported signals from the periphery, because they are induced by either colchicine or tight ligation. Conversely, axonally transported factors, either from the site of nerve injury or from the periphery, do not appear to be critical for the development of mechanical allodynia.

Animals↗

PubMed1993

Inhibition of posterior capsule opacification: the effect of colchicine in a sustained drug delivery system.

We investigated the effect of colchicine in a sustained drug delivery system on posterior capsule opacification (PCO) in rabbit eyes. A polymer matrix wafer, which diffused colchicine at a steady rate, was implanted in the capsular bag of 34 eyes after the lens material was removed by endocapsular phacoemulsification. Three different drug concentrations were used in the rabbit eyes, which were compared with control eyes containing the polymer matrix wafer without colchicine. The mean PCO score was highest in the control group without colchicine and increased steadily over 12 weeks. The rate of PCO formation in all eyes treated with colchicine was significantly lower than in the control group. There was no statistically significant improvement in PCO inhibition with the higher colchicine dosages. Side effects included inflammatory anterior chamber reaction and corneal and retinal complications and were most notable with the highest drug concentration. Slow release of colchicine reduces PCO formation in the rabbit. The optimal biocompatible dosage must be carefully determined and warrants further investigation.

Animals↗

PubMed2001

Kinetics of micronucleus induction and cytotoxic activity of colchicine in murine erythroblast in vivo.

In previous studies, we inferred some pharmacokinetic and pharmacodynamic parameters of alkylating agents and antimetabolites by comparing their kinetics of micronucleated polychromatic erythrocyte (MN-PCE) induction with the one obtained after the exposure to gamma rays in peripheral blood of mice, assuming that radiation acts immediately because it does not require absorption and distribution in the organism. According to our earlier studies, the kinetics of MN-PCE induction depends mainly on the following: (i) the cytotoxic effects that in turn could affect the duration of cell division; (ii) the pharmacokinetics including the metabolic activation requirement; and (iii) the mechanism of MN induction. The aim of the present study was to analyze the kinetics of MN-PCE induction by an aneuploidogen that induces micronuclei by acting on the achromatic spindle. The kinetics of MN-PCE induction by colchicine, as well as the reduction in the PCE frequency over time was determined in peripheral blood of mice treated with different doses of the aneuploidogen. The genotoxic effect, established as the area beneath the curve (ABC) of MN-PCE versus time-response, indicates an almost directly proportional relationship with respect to dose. Similarly, the relationship between dose and cytotoxic effect determined as the ABC of PCE versus time was inversely proportional, suggesting a relationship between both endpoints and doses administered. However, the number of cells affected by these two phenomena indicates that cytotoxicity is not necessarily caused, or at least not only by genotoxicity. The analysis of the kinetics of MN-PCE induction after the treatment with non-cytotoxic dose of colchicine, indicates that the MN-PCE appear in the blood stream at almost the same time, as occurs after the exposure to gamma rays; in spite of the differences in the cell cycle stage in which they can cause micronucleus (MN). Perhaps the fact that cells are not synchronized does not permit one to observe some difference in the time they appear in the blood. These results suggest that colchicine acts rapidly after exposure. The elimination half-life of colchicine is 17h, suggesting that colchicne is disposable for long time. With high doses of colchicine the pharmacokinetic parameters increases substantially. These data imply that low doses of colchicine are slightly cytotoxic, and that under this circumstances colchicines arrives rapidly to hemopoyetic tissues and acts for several hours.

Aneuploidy↗