ABSTRACT
The cytotoxicity of the alkaloid emetine was determined in six human cell lines that differ in the expression of ABC transporters, such as multiple drug resistance protein 1 (MDR1/ABCB1) and multidrug resistance associated protein 1 (MRP1/ABCC1). Emetine reveals a substantial cytotoxicity due to apoptosis that is inversely correlated with the expression of MDR1. Confluent Caco-2 cells with high MDR1 activity and the MDR1 over-expressing leukemia cell line CEM/ADR5000 are more resistant towards emetine (EC (50) 250 microM and 2 microM, respectively) than cells with a low expression of MDR1 (Jurkat cells, CCRF-CEM cells, HL-60 cells) or cells which over-express MRP1 (HL-60/AR) (EC (50) between 0.05 microM for CCRF-CEM and 0.17 microM for Jurkat cells). Apparently emetine is a substrate for MDR1 but not for MRP1. Furthermore, emetine is able to up-regulate the expression of MDR1 as shown IN VITRO by real-time PCR and transport activity studies.
Subject(s)
Antibiotics, Antineoplastic/analysis , Emetine/chemistry , ATP-Binding Cassette Transporters/pharmacology , Cell Line, Tumor , Emetine/antagonists & inhibitors , HumansABSTRACT
Ipecac syrup, prepared from a galentical ipecac, contains the nauseant alkaloids cephaeline and emetine. The involvement of receptors and serotonin- and dopamine-metabolizing enzymes in the emesis induced by ipecac syrup and these components was investigated. 1) In ferrets, the selective 5-HT3-receptor antagonist ondansetron (0.5 mg/kg, p.o.) prevented each emesis induced by TJN-119 (0.5 mL/kg, p.o.), cephaeline (0.5 mg/kg, p.o.) and emetine (5.0 mg/kg, p.o.), but the intraperitoneal administration of the selective dopamine D2-receptor antagonist sulpiride failed to significantly suppress the TJN-119, cephaeline and emetine-induced emesis at a dose of 0.1 mg/kg that blocked apomorphine-induced emesis. 2) In the receptor binding assays, cephaeline and emetine had a distinct affinity to 5-HT4 receptor, but no or weak affinity to 5-HT1A, 5-HT3, nicotine, M3, beta1, NK1, and D2 receptors. 3) Cephaeline and emetine did not affect activities of metabolic enzymes of 5-HT and dopamine (MAO-A, MAO-B, tryptophan 5-hydroxylase and tyrosine hydroxylase) in vitro. These results suggest that 5-HT3 receptor plays an important role in the emetic action of TJN-119, cephaeline and emetine, and the 5-HT4 receptor may be involved in their mechanisms.
Subject(s)
Emetics/pharmacology , Emetine/analogs & derivatives , Ipecac/pharmacology , Receptors, Serotonin/drug effects , Animals , Cell Line , Cricetinae , Dopamine/metabolism , Emetine/antagonists & inhibitors , Emetine/pharmacology , Ferrets , Guinea Pigs , Humans , Ipecac/antagonists & inhibitors , Male , Protein Binding , Rats , Receptors, Serotonin/metabolism , Receptors, Serotonin/physiology , Serotonin/metabolism , Serotonin Antagonists/pharmacology , Sulpiride/pharmacologyABSTRACT
The inhibition of protein synthesis in eukaryotic cells will prevent them from entering mitosis. Emetine inhibits peptide elongation. When it was added to asynchronous populations of Chinese hamster ovary (CHO) cells, the mitotic index decreased sharply 30 to 40 min later. It was found that the inhibitory effect of emetine could be reversed when it was removed and the reversibility was dependent on both the initial concentration of emetine and the pH of the medium. Cell populations that were blocked by emetine for up to 2h showed a four- to fivefold increase in mitotic index approximately 1 h after the emetine was removed. These results indicate that there is a point or period in G2 phase at which critical 'mitotic proteins' are being synthesized, and if their synthesis is interrupted cells will fail to enter mitosis.
Subject(s)
Emetine/pharmacology , Mitosis , Protein Biosynthesis , Animals , Antimetabolites , Cells, Cultured , Cricetinae , Cricetulus , Dose-Response Relationship, Drug , Emetine/antagonists & inhibitors , Female , Hydrogen-Ion Concentration , Leucine/metabolism , Mitosis/drug effects , Mitotic Index/drug effects , Ovary/cytology , RNA/biosynthesis , Uridine/metabolismSubject(s)
Behavior, Animal/drug effects , Caffeine/pharmacology , Central Nervous System/drug effects , Animals , Avoidance Learning/drug effects , Caffeine/administration & dosage , Caffeine/toxicity , Conditioning, Psychological , Emetine/antagonists & inhibitors , Guinea Pigs , Male , Reserpine/antagonists & inhibitorsABSTRACT
1. The mechanism of the inhibitory effect of dehydroemetine on the heart was investigated using (a) the spontaneously contracting isolated guinea-pig atrial preparation and (b), the electrically driven left atrial preparation.2. Dehydroemetine decreased the rate and amplitude of contraction of spontaneously contracting atria.3. Increasing the calcium concentration of the bath fluid to 28.2 mM abolished the effect of dehydroemetine on amplitude of contraction while the effect on rate persisted.4. Pretreatment with dehydroemetine increased the capacity of ouabain to induce arrhythmias in spontaneously contracting atria. Similarly pretreatment with ouabain augmented the inhibitory effect of dehydroemetine on spontaneous atrial activity.5. In the electrically driven left atrial preparation, dehydroemetine caused a decrease in contractile strength which was opposed by ouabail and by increased calcium concentration of the bath fluid.6. The effect of dehydroemetine on spontaneously contracting and on electrically driven atria was mimicked by adding excess potassium to the bath fluid.7. It was concluded that the effects of dehydroemetine on rate and contractility are, to a large extent, independent of one another. The effect on spontaneous rate is consistent with alteration of the potassium permeability of the myocardial cell membrane while the effect on contractility appears to be due to a decrease in the uptake of calcium from the medium by the myocardial cell.
Subject(s)
Calcium/pharmacology , Emetine/pharmacology , Heart/drug effects , Ouabain/pharmacology , Animals , Calcium/administration & dosage , Cell Membrane Permeability , Electric Stimulation , Emetine/administration & dosage , Emetine/antagonists & inhibitors , Female , Guinea Pigs , Heart Atria/drug effects , Heart Rate/drug effects , In Vitro Techniques , Male , Ouabain/administration & dosage , Potassium/pharmacologyABSTRACT
1. The mechanisms of the inhibitory effect of dehydroemetine on the heart was investigated using spontaneously contracting isolated guinea-pig atria.2. In normal Locke solution, dehydroemetine caused a reduction in the rate and amplitude of contraction of the atria. The effect was antagonized by adrenaline and augmented by acetylcholine.3. Increasing the potassium concentration of the bathing medium increased the inhibitory effect of dehydroemetine on the atria, while decreasing the potassium concentration antagonized the effect of dehydroemetine.4. The character of the inhibitory effect of dehydroemetine on the atria altered when the sodium concentration of the bathing solution was lowered to 75.6 mmol. In the normal sodium medium arrest of beat by dehydroemetine was gradual; in the low sodium medium, it was abrupt.5. In the low, as in the normal sodium medium, the inhibitory effect of dehydroemetine was more marked the higher the potassium concentration of the bathing medium.6. In both standard Locke solution and Locke solution containing 75.6 mmol sodium, the effect of dehydroemetine closely mimicked that obtained by adding excess potassium to the solution.7. On the basis of the foregoing it was suggested that dehydroemetine acts by increasing the permeability of the myocardial cell membrane to potassium thereby leading to the accumulation of potassium in the extracellular space.
