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1.
Toxicology ; 199(2-3): 137-43, 2004 Jul 01.
Article in English | MEDLINE | ID: mdl-15147788

ABSTRACT

The effects of polysorbate 80, a non-ionic surfactant widely used in pharmaceutical products, on rat thymocytes were examined to reveal its toxic property at the cellular level. Polysorbate 80 at concentrations of 1-100 microg/ml did not significantly affect the cell viability. This surfactant at 30 microg/ml or more augmented the intensity of fluo-3 fluorescence, indicating the increase in intracellular Ca(2+) concentration. Such an augmentation of fluo-3 fluorescence by polysorbate 80 was not seen under the Ca(2+)-free condition, suggesting that polysorbate 80 increased membrane Ca(2+) permeability. The concentration-dependent polysorbate 80 at 10 microg/ml or more attenuated the intensity of 5-chloromethylfluorescein, indicating a decrease in cellular content of glutathione by polysorbate 80. Furthermore, the agent at 1 microg/ml or more attenuated the intensity of bis-(1,3-dibutylbarbituric acid) trimethine oxonol fluorescence, being independent from the changes in membrane potential. This phenomenon indicates that polysorbate 80 at 1 microg/ml or more may attenuate the incorporation of anionic compounds into the membranes. It can be suggested that polysorbate 80 modifies some of membranes and intracellular physiological parameters without affecting the cell viability.


Subject(s)
Flow Cytometry/methods , Polysorbates/toxicity , Surface-Active Agents/toxicity , Thymus Gland/drug effects , Animals , Calcium/metabolism , Cell Culture Techniques , Cell Survival/drug effects , Dose-Response Relationship, Drug , Glutathione/metabolism , Rats , Rats, Wistar , Thymus Gland/metabolism , Thymus Gland/pathology
2.
Toxicology ; 195(1): 77-84, 2004 Jan 15.
Article in English | MEDLINE | ID: mdl-14698570

ABSTRACT

The effect of thimerosal, an organomercurial preservative in vaccines, on cerebellar neurons dissociated from 2-week-old rats was compared with those of methylmercury using a flow cytometer with appropriate fluorescent dyes. Thimerosal and methylmercury at concentrations ranging from 0.3 to 10 microM increased the intracellular concentration of Ca2+ ([Ca2+]i) in a concentration-dependent manner. The potency of 10 microM thimerosal to increase the [Ca2+]i was less than that of 10 microM methylmercury. Their effects on the [Ca2+]i were greatly attenuated, but not completely suppressed, under external Ca(2+)-free condition, suggesting a possibility that both agents increase membrane Ca2+ permeability and release Ca2+ from intracellular calcium stores. The effect of 10 microM thimerosal was not affected by simultaneous application of 30 microM L-cysteine whereas that of 10 microM methylmercury was significantly suppressed. The potency of thimerosal was similar to that of methylmercury in the presence of L-cysteine. Both agents at 1 microM or more similarly decreased the cellular content of glutathione in a concentration-dependent manner, suggesting an increase in oxidative stress. Results indicate that thimerosal exerts some cytotoxic actions on cerebellar granule neurons dissociated from 2-week-old rats and its potency is almost similar to that of methylmercury.


Subject(s)
Calcium/metabolism , Cerebellum/metabolism , Neurons/metabolism , Preservatives, Pharmaceutical/toxicity , Thimerosal/toxicity , Vaccines/chemistry , Animals , Cerebellum/cytology , Cerebellum/drug effects , Flow Cytometry , Fluorescent Dyes , Methylmercury Compounds/toxicity , Neurons/drug effects , Rats , Rats, Wistar
3.
Environ Toxicol ; 18(5): 321-6, 2003 Oct.
Article in English | MEDLINE | ID: mdl-14502585

ABSTRACT

The effect of PbCl2 on membrane potential and intracellular divalent metal cation concentrations of rat thymocytes was examined by flow cytometry. PbCl2 at concentrations of 0.3 microM or higher (up to 10 microM) produced persistent, dose-dependent hyperpolarization (decrease in the intensity of di-BA-C4 fluorescence). Removal of external Ca2+ did not significantly affect the PbCl2-induced hyperpolarization. Charybdotoxin, a specific antagonist of Ca(2+)-dependent K+ conductance, greatly attenuated the PbCl2-induced hyperpolarization. PbCl2 increased the intensity of fluo-3 fluorescence under both normal Ca2+ and nominally Ca(2+)-free conditions. These results suggest that Pb2+ enters thymocytes, causing an increase in fluo-3 fluorescence, and activates Ca(2+)-dependent K+ channels, resulting in hyperpolarization. The persistent activation of K+ channels by Pb2+, leading to persistent hyperpolarization, may be one mechanism whereby Pb2+ alters immune function, as membrane potential changes influence physiological functions of lymphocytes.


Subject(s)
Lead/toxicity , Potassium Channels/drug effects , Thymus Gland/cytology , Animals , Dose-Response Relationship, Drug , Flow Cytometry , Lead/pharmacokinetics , Membrane Potentials/drug effects , Potassium Channels/physiology , Rats , Rats, Wistar
4.
J Pharmacol Sci ; 91(1): 83-6, 2003 Jan.
Article in English | MEDLINE | ID: mdl-12686735

ABSTRACT

To test the possibility that micromolar formaldehyde, a metabolite of methanol derived from aspartame, exerts cytotoxicity, its effect on rat thymocytes was examined under the in vitro condition using a flow cytometer. Incubation of thymocytes with formaldehyde at 100 micro M or more for 24 h significantly increased the populations of shrunken cells and cells with hypodiploid DNA. The peak blood concentration of methanol in human subjects administered abuse doses of aspartame has been reported to exceed 2 mg/dL (625 micro M). It would increase the population of thymocytes undergoing apoptosis if formaldehyde at 100 micro M or more appears in the blood after administration of aspartame.


Subject(s)
Formaldehyde/pharmacology , T-Lymphocytes/drug effects , T-Lymphocytes/ultrastructure , Animals , Apoptosis/drug effects , Aspartame/adverse effects , Aspartame/pharmacokinetics , Cell Death/drug effects , Cell Size/drug effects , DNA/metabolism , In Vitro Techniques , Rats , Rats, Wistar , Thymus Gland/cytology , Thymus Gland/drug effects
5.
Environ Toxicol Pharmacol ; 15(1): 45-51, 2003 Dec.
Article in English | MEDLINE | ID: mdl-21782679

ABSTRACT

Lead is ubiquitous in our environment and lead poisoning is a major public health problem worldwide. In this study, to see if intracellular Pb(2+) induces the exposure of phosphatidylserine in rat thymocyte membranes, we have examined the effect of PbCl(2) on rat thymocytes treated with A23187 using a flow cytometer with appropriate fluorescent indicators under nominally-Ca(2+)-free condition. PbCl(2) at 1-30 µM dose-dependently induced the exposure of phosphatidylserine on outer membranes, associated with increasing the concentration of intracellular Pb(2+). The potency of intracellular Pb(2+) to induce the apoptotic change in thymocyte membranes seems to be greater than those of intracellular Ca(2+) and Cd(2+). Results suggest that intracellular Pb(2+) triggers apoptosis of rat thymocytes. This action of Pb(2+) may be one of mechanisms for the lead-induced changes in immunity.

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