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PubMed1978

Modification of UV-induced mutation frequencies in Chinese hamster cells by dose fractionation, cycloheximide and caffeine treatments.

Chinese hamster (V79) cells were irradiated with a fractionated regime of ultraviolet light (UV1 + UV2). The fractionation of a UV dose always increased the colony-forming ability but reduced (or it did not change) the mutation frequencies. Treatment with cycloheximide between the two UV irradiations resulted in two types of effects, depending on the protocols used. Long exposures to cycloheximide (i.e., greater than 6 h) for the entire period between UV1 and UV2 or partial treatment of cycloheximide (i.e., 3 h) long before UV2 always resulted in reduced colony-forming ability and enhanced or unchanged mutation frequencies. Exposure to cycloheximide for the entire period in the short fractionated regime (i.e., 4 h) between UV1 and UV2 or partial treatment of cycloheximide just prior to UV2 tended to give the opposite effects. Caffeine treatment before UV2, with or without UV1, significantly increased the mutation frequencies. These results suggest that an error-free postreplication repair system exists in Chinese hamster cells which is inhibitable by particular cycloheximide or caffeine treatments.

Caffeine↗
PubMed1994

Effects of cycloheximide on chromatin condensations and germinal vesicle breakdown (GVBD) of cumulus-enclosed and denuded oocytes in cattle.

To determine if newly synthesized protein is imperative for the resumption of meiosis in bovine follicular oocytes collected from small antral follicles, cumulus-enclosed and denuded oocytes were cultured in TCM-199 both with and without various concentrations of the protein synthesis inhibitor, cycloheximide. After 11 h of culture in inhibitor-free medium, all oocytes had undergone germinal vesicle breakdown (GVBD). However, when concentrations of more than 1.0 mug/ml cycloheximide were added to the medium, the meiotic resumption of bovine oocytes was completely blocked. This inhibitory effect of cycloheximide was fully reversible after removal of the inhibitor from maturation media. Germinal vesicle breakdown following removal of cycloheximide occurred twice as fast as in the control medium. Nevertheless, when oocytes were arrested at the germinal vesicle (GV) stage by cycloheximide, a significantly higher proportion of chromatin condensation (40 to 57%) was observed in denuded oocytes than in cumulus-enclosed oocytes (11 to 22%). Thus the cycloheximide treatment could not prevent the chromatin condensation in only denuded oocytes. We conclude that protein synthesis is a prerequisite for GVBD in bovine follicular oocytes and that cumulus cells are responsible for the complementary regulation of the chromatin condensation at the GV stage, regardless of protein synthesis in the oocytes.

Journal Article↗
PubMed1999

Superinduction of Oxidized Tryptophan-Inducible Cytochrome P450 1A1 by Cycloheximide in Hepa lclc7 Cells.

Previous studies from this laboratory have shown that L-tryptophan, after oxidation by either ultraviolet (UV) irradiation or ozone, causes induction of cytochrome P450 (CYP)1A1 mRNA, protein, and the corresponding 7-ethoxyresorufin O-deethylase (EROD) activity in wild type mouse hepatoma cells, Hepa lclc7 (Hepa-1), through the aryl hydrocarbon receptor (AhR). In the present study, we have examined the effect of temporary inhibition of protein synthesis by cycloheximide on oxidized tryptophan inducible CYP1A1 mRNA, protein, and EROD activity in Hepa-1 cells. The results demonstrate that combined exposure of wild-type Hepa-1 cells to either UV- or ozone-oxidized tryptophan and cycloheximide causes an increase in CYP1A1 mRNA, protein, and EROD activity, which is greater than the sum of the increases that were observed by exposure to each compound alone. The increase in EROD activity is dependent upon the dose and duration of cycloheximide treatment and is prolonged by actinomycin D when the latter compound was administered after removal of cycloheximide. Studies carried out to investigate the mechanism of this superinduction using various mutants of Hepa-1 cells, which are defective in either the AhR or AhR nuclear translocator protein indicated that the superinduction of oxidized tryptophan inducible EROD activity by cycloheximide occurs through the AhR. This is the first demonstration that oxidized tryptophan, in the presence of cycloheximide, causes superinduction of transcription of the Cyp1a1 gene with concomitant increase of CYP1A1 protein and EROD activity in Hepa-1 cells.

Journal Article↗
PubMed1997

Cycloheximide prevents apoptosis, reactive oxygen species production, and glutathione depletion induced by transforming growth factor beta in fetal rat hepatocytes in primary culture.

We have previously reported that transforming growth factor-beta (TGF-beta) induces apoptosis in fetal hepatocytes in primary culture. This effect was found to be associated with an increase in intracellular reactive oxygen species (ROS) and a lowering of total cellular reduced glutathione (GSH). In this study, we investigated whether protein synthesis plays a role in these TGF-beta-induced effects. When fetal hepatocytes were incubated in the presence of cycloheximide, a specific protein synthesis inhibitor, TGF-beta-induced apoptosis was completely blocked. The overall intracellular oxidized state of the cells, when measured using either 2',7'-dichlorofluorescein diacetate (DCFH) by laser-scanning confocal microscopy, or both DCFH and hydroethidine (DHE) by flow cytometric analysis, was increased transiently after the addition of TGF-beta. This increase was abolished by incubation of the cells in the presence of cycloheximide. Furthermore, the decrease in the total cellular GSH content induced by TGF-beta in these cells was not observed when cycloheximide was present. Cycloheximide effect was not associated with an enhancement of cysteine and restoration of cellular glutathione level, because inhibition of GSH synthesis with buthionine sulfoximine (BSO) did not prevent the cycloheximide protective effect. Experiments performed to check whether Fas (APO-1) ligand might be the protein that needs to be synthesized have indicated that this possibility can be excluded. All these findings suggest that apoptosis elicited by TGF-beta in fetal hepatocytes requires the synthesis of an unknown protein before ROS production, glutathione loss, and oxidative stress.

Animals↗
PubMed1988

Time sequence of germinal vesicle breakdown in pig oocytes after cycloheximide and P-aminobenzamidine block.

All porcine oocytes cultured 20 hr in medium with 10 micrograms/ml cycloheximide rested in the germinal vesicle (GV) stage but with the highly condensed bivalents in nucleoplasm. When these oocytes were washed and cultured in the control medium for 2, 4, and 6 hr, germinal vesicle breakdown (GVBD) was completed in 0, 86, and 100% of them, respectively. When similarly inhibited oocytes cultured successively only 2.5 hr in the control medium were given again in cycloheximide enriched medium (3.5 hr), nearly all of them reached late diakinesis stage again. It means that oocytes cultured for 20 hr and washed free of this inhibitor of protein synthesis completed GVBD rapidly (4 hr) and protein synthesis crucial for nuclear membrane disintegration occurred already during the first 2 hr after washing of inhibitor. All oocytes cultured for 20 hr in medium with 1 mM p-aminobenzamidine rested in GV with chromatin around the compact nucleolus. The successive culture in cycloheximide (20 hr) and p-aminobenzamidine (10 hr) prevented GVBD in all oocytes, too. In contrast, when the oocytes washed after cycloheximide block (20 hr) were cultured in p-aminobenzamidine enriched medium 2 and 3 hr and again for 6 hr in cycloheximide medium, the nuclear membrane dissolved in 62 and 68% of oocytes, respectively. These data suggest that inhibition of protein synthesis in pig oocytes does not prevent the high condensation of bivalents in GV. However, nuclear membrane breakdown requires the successive protein synthesis and proteolysis.

Amidines↗
PubMed1978

Genetic and biochemical analysis of cycloheximide resistance in the fungus Podospora anserina.

Genetic analysis of cycloheximide-resistant mutants has shown that at least three genes control the resistance to cycloheximide in Podospora anserina and that the antibiotic resistance is recessive to sensitivity. In vitro and in vivo studies of protein synthesis indicated that for two mutants cycloheximide resistance is associated with the ribosomes. For one of these mutants, the elongation step in protein biosynthesis is insensitive to cycloheximide over a wide range of concentration. In this mutant the resistance to cycloheximide is a property of the 60S subunit.

Ascomycota↗
PubMed1980

Muliple sites of action of cycloheximide in addition to inhibition of protein synthesis in Physarum polycephalum.

The specificity action of cycloheximide was tested using a cycloheximide resistant mutant of Physarum polycephalum. This resistance has previously been shown to reside with the ribosomes, making cytoplasmic protein synthesis refractile to the action of the drug. We show here that cycloheximide in the mutant strain causes specific alterations in metabolism without influencing the growth rate. These are: 1. lowered specific activity of glutamate dehydrogenase during starvation, 2. alteration of the molecular weight of glutamate dehydrogenase, 3. inhibition of uptake of amino acids from the medium into the internal pools. Possible explanations for these effects of cycloheximide outside of protein synthesis per se are considered. We conclude that cycloheximide may not be considered a specific inhibitor of protein synthesis, and that a causal relationship between protein synthesis and any biological process cannot be claimed unless such specificity is demonstrated in each case, preferably by use of mutants.

Amino Acids↗
PubMed1996

The role of enteric bacteria in the pathogenesis of fatal cycloheximide intolerance in mice pretreated with dexamethasone, promethazine or nordihydroguaiaretic acid.

As an incidental finding in a separate, ongoing investigation, dexamethasone was shown to sensitise mice fatally to a later challenge with a normally-tolerated dose of cycloheximide. This phenomenon is described here; it is also shown that two unrelated agents, namely promethazine and nordihydroguauaretic acid, duplicated this sensitising effect of the steroid. The three drugs have in common the ability to inhibit powerfully the synthesis of tumour necrosis factor-alpha in response to lipopolysaccharide, and it is suggested that this property is linked to their ability to induce fatal cycloheximide intolerance. Such drug-pretreated mice were protected if given dexamethasone at the time of cycloheximide challenge. An equal degree of protection was conferred on such animals by oral antibiotic treatment known to eliminate the aerobic intestinal flora. This indicated that the three agents induced fatal susceptibility to cycloheximide through the agency of the gut flora. It is proposed that the three drugs act by impairing the hepatic mechanism which normally removes portal vein-borne endogenous lipopolysaccharide, leading to systemic distribution of lipopolysaccharide, which is known from previous work, using a small dose of intraperitoneally injected lipopolysaccharide, to render mice fatally susceptible to a later cycloheximide challenge.

Animals↗
PubMedDate not supplied

Insulinlike growth factor-1 inhibits cell death induced by cycloheximide in MCF-7 cells: a model system for analyzing control of cell death.

Prolonged exposure of cells to the potent protein synthesis inhibitor cycloheximide terminates in cell death. In the present study we investigated the effect of insulinlike growth factor-1, insulin, and epidermal growth factor on cell death induced by cycloheximide in the confluent MCF-7 cells, and correlated this effect to the inhibition rate of protein synthesis. Cell death was evaluated by measuring either dead cells by the trypan blue dye exclusion test or by the release of lactic dehydrogenase into the culture medium. After 48 h incubation, cycloheximide (10 to 50 micrograms/ml) was shown to induce cell death in a concentration-dependent manner. Insulinlike growth factor-1, at physiologic concentrations (0.2 to 5 ng/ml), reduced this cell death. Insulin at supraphysiologic concentrations (1 to 10 micrograms/ml) mimicked the effect of insulinlike growth factor-1, whereas epidermal growth factor (10 to 50 ng/ml) had no effect. More than 90% of protein synthesis measured by [3H]leucine incorporation was inhibited by 10 to 50 micrograms/ml cycloheximide. Insulinlike growth factor-1 and insulin at the concentrations that reduced cell death to control level, had no effect on the protein synthesis inhibition rate induced by cycloheximide. These results indicate that inhibition of cell death by insulinlike growth factor-1 does not depend on protein synthesis and may be mediated via a posttranslational modification effect.

Breast Neoplasms↗
PubMed1985

Decrease by cycloheximide of calcium binding and nonesterified fatty acids in rat-intestinal Golgi-enriched membrane fractions.

Rat intestinal Golgi-enriched membrane fractions bind more Ca2+ than do basolateral and microvillus-enriched membrane fractions, and this uptake is reduced by vitamin D-deficiency. The effect of the protein synthesis inhibitor, cycloheximide, on this Ca2+ binding was determined in rat fed a normal, vitamin D-sufficient diet. Cycloheximide, 1.5 mg/kg, rapidly reduced protein synthesis (measured by [3H]leucine incorporation) to 12% of control values within 15 min, but Ca2+ binding diminished gradually to 50% of control values by 60 min. Ca2+ transport across gut sacs was also decreased. The reduction in Ca2+ binding was not due to an alteration in vesicle morphology or to a direct effect of cycloheximide. Nonesterified (free) fatty acids, the probable binding sites for Ca2+ in these membrane fractions, were reduced by cycloheximide to 48% of control values by 60 min. There was no significant change in total lipid phosphate. Cycloheximide may affect the synthesis of proteins necessary for the presence of nonesterified fatty acids in these Golgi membranes.

Animals↗
PubMed1989

Effect of minaprine on cycloheximide-induced amnesia in mice.

The effects of minaprine on cycloheximide-induced amnesia were investigated in a step-down passive avoidance task in mice. Minaprine significantly improved cycloheximide-induced amnesia. This effect was inhibited by scopolamine, but was potentiated by physostigmine. The anti-amnesic effect of minaprine on the cycloheximide-induced memory impairment was also antagonized by a serotonin (5-HT) releaser, p-chloroamphetamine, and by a 5-HT precursor, 5-hydroxytryptophan, whereas a 5-HT1A-selective agonist, 8-hydroxy-2-(di-n-propylamino)tetralin, was inactive. The memory-improving effect of minaprine on cycloheximide-induced amnesia was potentiated by a selective 5-HT2 antagonist, ritanserin. These results suggest that the beneficial effect of minaprine on cycloheximide-induced amnesia may be related not only to cholinergic but also serotonergic neuronal systems (5-HT2 receptors).

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1983

[3H]lysine incorporation into protein of hemisected, cycloheximide-treated spinal cord.

A single application of a protein synthesis inhibitor, puromycin, in the lesion site of a spinal hemisection transiently decreases protein incorporation for less than 24 h and results in axonal sprouting and dendritic and synaptic stability for at least 60 days. In this study we characterized the protein-altering properties of single applications of a different protein synthesis inhibitor, cycloheximide, for comparison. The protein incorporation of [3H] lysine into hemisected rat spinal cord (left side, T2) treated with cycloheximide (100 micrograms/ml in Gelfoam sponge placed in wound at time of lesion) was tested 3 h, 6 h, 12 h, 1, 3, 7, and 14 days later and compared with that in 0.9% saline in Gelfoam implants as normal controls (N = 54). One hour prior to utilization, the animals were injected subcutaneously with 200 mu Ci L-[4,5(n)-3H]lysine monohydrochloride. No treatment-related differences in brain radioactivity were noted at any time postoperation. In spinal cord, inhibition of amino acid uptake by cycloheximide was not demonstrable at 3 h after hemisection, but could be detected from 6 h to 1 day after implantation. During that time, the TCA-soluble radioactivity at the lesion site was greater than in control animals (P less than 0.05). These results suggest that as with puromycin, morphologic effects produced by cycloheximide on spinal cord regeneration may correspond to chemical events which occurred within the first 24 h after cord hemisection and cycloheximide treatment.

Animals↗
PubMed1985

The effect of cycloheximide, heparin and ancrod on mice given Ehrlich ascites tumour cells intravenously.

Mice injected intra-venously with Ehrlich ascites tumour cells showed a fatal susceptibility to normally-tolerated doses of cycloheximide when the latter was given at the following times after the tumour cells--2 h, 24 h, 48 h, and 72 h. When the interval between tumour cell injection and cycloheximide challenge was extended to 1 week or 3 weeks (at which latter time mice have clinical "metastatic" neoplasia), no such susceptibility was shown. In the case of the 2 h interval between tumour cells and cycloheximide (and also when cycloheximide was given 2 h before tumour cells), the lethal syndrome was prevented by heparin treatment and also by Ancrod defibrination. This strongly suggests that heparin is effective by virtue of its anticoagulant properties, and that fibrinogen-to-fibrin conversion is an essential step in the pathogenesis. Neither heparin nor Ancrod confer any protection when used in the syndrome consequent upon cycloheximide challenge 24 h after tumour cell injection, which indicates that, in this case, the conversion of fibrinogen to fibrin is not an essential step in determining the fatal outcome.

Ancrod↗
PubMed1989

The roles of glucocorticosteroid and of fibrinolytic activity in the development of bilateral renal cortical necrosis in cycloheximide-treated mice challenged with a submicrogram dose of endotoxin.

Mice given cycloheximide and 0.2 microgram of endotoxin simultaneously developed ischaemic bilateral renal cortical necrosis as part of a fatal syndrome. Endotoxin given 2 h after cycloheximide, although fatal, failed to produce renal cortical necrosis. Investigation suggested that, following endotoxin challenge in cycloheximide-treated mice, the occurrence or non-occurrence of bilateral renal cortical necrosis was determined by the concentration of circulating glucocorticoids at the time of endotoxin challenge. Thus, below a certain, as yet undefined, glucocorticoid concentration, endotoxin does not cause renal cortical necrosis in cycloheximide-treated mice. Inhibition of the fibrinolytic system by epsilonaminocaproic acid (EACA) indicated that protection against renal cortical necrosis was directly mediated by increased fibrinolytic activity. Since this increased activity occurred during a period of profound cycloheximide-mediated inhibition of protein synthesis, it was postulated that pre-existing plasminogen activator was released from inhibition, and that this release could only occur when the glucocorticoid concentration fell below a certain critical value.

Aminocaproic Acid↗
PubMed1994

Dose-related effects of cycloheximide on delayed neuronal death in the gerbil hippocampus after bilateral transitory forebrain ischemia.

Degeneration of dendrites followed by punctate chromatin condensation in the CA1 area of the hippocampus is a characteristic of delayed neuronal death following bilateral forebrain ischemia. The effects of the protein synthesis inhibitor cycloheximide on delayed neuronal death following 20 min of bilateral forebrain ischemia were examined in the gerbil hippocampus at the 4th day of reperfusion. Low doses of cycloheximide beginning 10 min after ischemia (1.0 microgram/g body weight in saline followed by 1.0 microgram/g every 24 h) reduced the number of dying cells in the CA1 area, whereas high doses (2.0 micrograms/g, followed by 1.0 microgram/g every 12 h) increased the number of dying cells. No effects were seen when a single dose of cycloheximide was injected 1 h before ischemia. These results indicate that the effects of cycloheximide are dose-dependent, low doses reduce, high doses increase cell death. These findings also indirectly suggest that protein synthesis may play a role in the extent of delayed neuronal death. Some involved proteins could be heat shock proteins, which are induced after ischemia and had been correlated with increased resistance to injury. However, changes of heat shock immunoreactivity in the postischemic hippocampus were not seen in the present study following cycloheximide injection.

Animals↗
PubMed1983

Prevention of lithocholate--induced cholestasis by cycloheximide, an inhibitor of protein synthesis.

Our previous investigations have shown that lithocholic acid (LCA)-induced cholestasis is associated with an increased synthesis of microsomal cholesterol which is transported with LCA and incorporated in the bile canalicular membrane. As the significance of these changes remains unknown the effect of interference with microsomal protein synthesis and/or with the cellular transport of cholesterol was studied. Male Wistar rats were injected i.p. with cycloheximide at the dose of 15 micrograms/100 g BW 3 times over a 24-hour period. After cannulating the common bile duct and collecting bile for one hour, the animals were either injected i.v. with 12 mumoles C14-LCA/100 g BW or with a 7.5% albumin solution and bile was collected for another hour. LCA injection in untreated animals reduced bile flow by more than 90% of control values. In contrast, bile flow in the group treated with cycloheximide and LCA was normal and did not differ from that of animals given cycloheximide alone. Bile salt secretion rate was increased in the cycloheximide-LCA group over the control groups. This was mainly due to the secretion of more than 80% of the injected LCA and was confirmed by the distribution of the radioactivity. By electron microscopy, the liver in the cycloheximide-LCA group did not show any of the well defined changes associated with LCA-induced cholestasis. These data suggest that microsomes play an important role in the pathogenesis of LCA cholestasis and that inhibition of microsomal protein synthesis can prevent its development.

Animals↗
PubMed1991

Effects of caffeine and cycloheximide during G2 prophase in control and X-ray-irradiated human lymphocytes.

The effect of caffeine and cycloheximide during the G2 phase on frequency of chromosomal aberrations and G2 duration was studied in control and X-ray-irradiated human lymphocytes in vitro. Caffeine treatments alone increase the frequencies of chromatid breakage and decrease the average G2 duration in control and X-ray-irradiated lymphocytes (40 R). Both caffeine effects are reversed by 0.5 micrograms/ml cycloheximide in combination treatments. Cycloheximide treatments alone prolong G2 duration in control as well as in X-ray-irradiated lymphocytes although no improvement in chromosome repairing by this inhibitor of protein synthesis was observed under the conditions of our experiments. We propose that the cycloheximide effect is associated with a low level of mitotic factors, required for the entrance into mitosis, which is maintained at a higher level in caffeine treatment alone. Finally, G2 delay has generally been associated with certain genome damage. The fact that the caffeine and cycloheximide effects on X-irradiated lymphocytes are also present in control lymphocytes (without X-rays) suggests that control of the G2 duration constitutes one of the mechanisms involved in DNA repair operating during the G2 phase.

Antimutagenic Agents↗
PubMed1976

Cooperative alignment of nu bodies during chromosome replication in the presence of cycloheximide.

50% of control DNA is resistant to staphylococcal nuclease after digestion in isolated nuclei, while only 25% of the labeled DNA made in the presence of cycloheximide is resistant to nuclease. Nevertheless, cycloheximide DNA is folded into normal chromosomal subunits as evidence by the observation that it generates nuclease limit-digest DNA fragments that are indistinguishable from controls. These results indicate that cycloheximide chromatin is associated with half the number of normal nu bodies. These nu bodies are probably recycled from the parental chromosome. Partial nuclease digestion of cycloheximide chromatin reveals that a normal pattern of monomer and multimer DNA fragments is generated up to octamers. The data are consistent with the idea that in the presence of cycloheximide, recycled parental histones become cooperatively aligned along the daughter double helices.

Chromatin↗