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[The effect of glucose and cycloheximide on glycerolipid biosynthesis in the rat liver].

Glucose and cycloheximide activated biosynthesis of phospholipids and, especially, of triacylglycerols involving 14C-acetate in rat liver tissue in vivo. Starvation did not affect the glycerolipid biosynthesis but decreased markedly the cholesterol production. In liver tissue of starved rats cycloheximide activated synthesis of glycerolipids and inhibited the cholesterol synthesis. Administration of glucose into the animals under conditions of their satiation augmented the fatty acid synthesis; the activating effect of cycloheximide was more distinct as compared with glucose. In satiated animals the most part of the label was incorporated into glycerolipid fatty acids after glucose and cycloheximide administration. Starvation inhibited synthesis of fatty acids with simultaneous activation of the glycerolipid glycerol production; cycloheximide activated still further the glyceroneogenesis. Both glucose and cycloheximide activated biosynthesis of palmitic and oleic acids of glycerolipids and inhibited the arachidonic acid synthesis. Similarity in the effect of glucose and cycloheximide on the glycerolipid biosynthesis might occur due to stimulation of glyceroneogenesis and to augmented production of alpha-glycerophosphate, which in turn increased the fatty acid esterification.

Animals↗
PubMed1994

Cycloheximide inhibits the cytotoxicity of paclitaxel (Taxol).

Treatment of human breast (MCF-7) and lung (A549) adenocarcinoma cell lines with 10 micrograms/ml cycloheximide provided substantial protection from paclitaxel-induced cytotoxicity. Addition of cycloheximide to cells at 0, 6, 12 or 18 h into a 24 h exposure to paclitaxel resulted in cytotoxicity similar to that found in cells treated with paclitaxel alone for only 0, 6, 12 or 18 h, respectively. DNA flow cytometry showed that paclitaxel blocked cells in G2/M. Mitotic index studies demonstrated that paclitaxel arrested cells in mitosis and that prolonged exposure to paclitaxel resulted in the development of multiple micronuclei. Concurrent incubation of cells in cycloheximide prevented the development of a G2/M block, mitotic arrest and micronuclei formation. The addition of cycloheximide to cells at 6 or 12 h into a 24 h exposure to paclitaxel reduced the degree of G2/M block to that produced by incubation of cells in paclitaxel alone for only 6 or 12 h. Mitotic index studies confirmed that cells treated with cycloheximide during paclitaxel exposure had a marked reduction in the percentage of cells in mitosis. However, the percentage of paclitaxel-treated cells which had multiple micronuclei was increased in cells treated with cycloheximide. These results indicate that entry into mitosis is a prerequisite for paclitaxel-induced cytotoxicity and that cycloheximide reduces cytotoxicity due to paclitaxel by preventing cells from entering mitosis. However, once cells have entered mitosis in the presence of paclitaxel, protein synthesis is not required for the development of multiple micronuclei and cytotoxicity.

Adenocarcinoma↗
PubMed1993

Cycloheximide induces the alpha 1B adrenergic receptor gene by activation of transcription in DDT1 MF-2 smooth muscle cells.

alpha 1-Adrenergic receptors play important roles in mediating a wide range of important cellular responses; regulation of expression of these receptors may have pathophysiological significance in diseases such as hypertension. In order to pursue understanding of mechanisms involved in the regulation of expression of alpha 1 receptors, the effects of protein synthesis inhibitor cycloheximide on alpha 1B receptor gene expression were examined in DDT1 MF-2 smooth muscle cells. Cycloheximide markedly induced accumulation of the alpha 1B receptor mRNAs in a concentration- and time-dependent manner as detected by Northern blotting assays. The increased accumulation of alpha 1B receptor mRNA could be detected at 1 hr (1.7 +/- 0.2-fold) and the maximal accumulation occurred at 6 hr (5.4 +/- 0.3-fold, p < 0.01). Nuclear runoff assays reveal that cycloheximide markedly increased the transcriptional rate of the alpha 1B receptor gene. The stability of alpha 1B receptor mRNAs measured by RNase protection assays was essentially unchanged by cycloheximide. Incubation of DDT1 MF-2 cells with two additional protein synthesis inhibitors, anisomycin and emetine, had similar effects to those of cycloheximide. However, a further inhibitor, puromycin, did not induce alpha 1B receptor mRNAs when protein synthesis was almost completely inhibited. Furthermore, puromycin did not inhibit the capacity of cycloheximide to induce transcription of the alpha 1B receptor gene. These observations suggest that cycloheximide induces alpha 1B receptor gene expression through direct activation of gene transcription rather than inhibition of protein synthesis.

Animals↗
PubMed1979

Kinetics of the cycloheximide-induced phase changes in the biological clock in Gonyaulax.

Cycloheximide, an inhibitor of protein synthesis on cytoplasmic ribosomes in eukaryotes, is shown to shift the phase of the circadian rhythm in stimulated bioluminescence in the marine dinoflagellate Gonyaulax polyedra. Kinetic analysis of the phase changes shows that this effect may be subdivided into two distinctly different and well-separated parts. The first (early) phase change occurs with 15-min exposure to cycloheximide and is saturated at low concentrations ( approximately 10 nM). The second (late) phase changes requires about 150 min of exposure to cycloheximide and is saturated at 0.36 muM cycloheximide. Twenty-times-higher concentrations cause no further phase changes. The magnitudes of both early and late phase changes depend on the time of day when the cells are exposed to cycloheximide. Early phase changes vary from 5 hr advance at circadian time (CT) 20 to 1 hr delay at CT 12; late phase changes are larger, the maximal advance being 12 hr at CT 16 and the greatest delay, 10 hr at CT 14. It is proposed that the early phase changes are caused by alterations in the ion distribution across membranes as a consequence of the permeation of cycloheximide. Late phase changes may be the result of inhibition of protein synthesis.The phase response curve for the late phase change is identical to that obtained with saturating light pulses in otherwise constant darkness in Gonyaulax. Maximal phase changes drive the clock into the part of the circadian cycle between CTs 4 and 9. Perturbations in this part of the circadian cycle are without effect on phase. Incubation of Gonyaulax with cycloheximide for a critical duration at a critical time induces arhythmicity, but longer exposures to the inhibitor at the same time do not. This observation suggests the existence of a singularity in the circadian clock of Gonyaulax.

Journal Article↗
PubMed1975

Photocontrol of the Germination of Onoclea Spores: III. Analysis of Germination Processes by Means of Cycloheximide.

Possible involvement of protein synthesis in the germination of Onoclea sensibilis spores was investigated by temporarily applying 0.1 mm cycloheximide before and after photoinduction. Cycloheximide was shown to inhibit protein synthesis, but not to act as an uncoupler of respiration. When cycloheximide was added before or shortly after photoinduction, spore germination was inhibited with the half-maximal inhibition attained in 30 to 45 minutes and the maximal inhibition in 2 hours of incubation. When the time of the inhibitor treatment was delayed after photoinduction, the spores escape from the inhibitory effect of cycloheximide slowly during the first 8 hours and abruptly thereafter with a half-maximal time of 10 hours. If spores are washed free of exogenous cycloheximide and subsequently irradiated, their ability to germinate can be reinstated in distilled water with a half-maximal time of 12 hours. The kinetics of recovery were identical and of apparent first order, regardless of whether cycloheximide treatments were given before or after photoinduction. These results are interpreted to indicate that the normal course of germination of Onoclea spores requires the continuous synthesis of a short lived enzyme that functions in the germination processes at about 10 hours after photoinduction. The cycloheximide-sensitive step follows in the germination processes an anaerobiosis-sensitive step, but precedes the time of acetocarmine uptake or visible signs of protrusion.

Journal Article↗
PubMed1981

Cycloheximide resistance in carrot culture: a differentiated function.

Cultured carrot cells grow as unorganized callus tissue in medium containing auxin. Upon removal of the auxin from the medium, they grow in an organized manner and differentiate into embryos. In the normal cell line, W001C, the callus growth can be inhibited by cycloheximide, but the embryonic growth cannot. A variant cell line, WCH105, whose callus growth is resistant to cycloheximide, was isolated. The mechanism of cycloheximide resistance in embryos of both lines and in WCH105 callus was found to be cycloheximide inactivation. In addition to auxin, bromodeoxyuridine can also promote callus growth in carrot culture. Callus cultures maintained by bromodeoxyuridine behave the same as do those maintained by auxin. WCH105 callus is resistant, whereas W001C callus is sensitive to cycloheximide inhibition. Except for the onset of embryogenesis, cycloheximide inactivation is expressed throughout the embryo developmental stages up to the plantlets. These results suggest that cycloheximide inactivation is a function expressed in the differentiated, but not in the undifferentiated, tissues.

Journal Article↗
PubMed1998

PAP gene transcription induced by cycloheximide in AR4-2J cells involves ADP-ribosylation.

We report in this paper that cycloheximide induces PAP mRNA expression in the pancreatic acinar cell line AR4-2J in a dose- and time-dependent manner. We analyzed whether stabilization of the PAP mRNA or the direct induction of its transcription contributed to the induction of PAP mRNA expression by the drug. We first infected the cells, which do not express PAP mRNA constitutively, with a recombinant adenovirus in which the PAP cDNA was subcloned downstream of the CMV promotor, to obtain high levels of transcript. Then, transcription was pharmacologically blocked, the cells were treated with cycloheximide, and the PAP mRNA concentration was monitored over 8 h by Northern blot. PAP mRNA concentration remained unchanged for 4 h and then decreased in both cycloheximide-treated and control cells, ruling out a significant contribution of posttranscriptional regulation in cycloheximide induction. Direct regulation of gene transcription is therefore likely and we investigated whether it could involve ADP-ribosylation. Cycloheximide-induced cells were treated with two chemical inhibitors of poly(ADP-ribose) polymerase. 3-Aminobenzamide inhibited 75% of PAP gene induction and 4-hydroxyquinazolone, the highly specific inhibitor of the enzyme, blocked almost completely PAP expression, suggesting that ADP-ribosylation was indeed required for the upregulation of PAP gene expression by cycloheximide.

Acute-Phase Proteins↗
PubMed1983

Inhibition of insulin-stimulated xylose uptake in rat soleus muscle by cycloheximide.

Cycloheximide (20-200 mg/l) did not affect basal D-[U-14C]xylose uptake by rat soleus muscle (2.4 +/- 0.2 mumol . g-1 . h-1). However, the stimulatory effect of insulin on sugar transport was progressively reduced from 375% above basal in control muscles to 170% in muscles exposed to 200 mg cycloheximide/l but above this concentration cycloheximide inhibited basal xylose uptake without further effect on the incremental effect of insulin. Cycloheximide affected the insulin dose-response curve both by depressing insulin sensitivity and by reducing the maximum stimulatory effect of the hormone. In contrast to the inhibition of insulin action, which increased progressively over the range 20-200 mg cycloheximide/l, muscle protein synthesis was inhibited maximally at a concentration of 10 mg/l. Cycloheximide also inhibited the insulinomimetic effects of anoxia, 2:4-dinitrophenol, salicylate, cooling, hydrogen peroxide, diamide, vitamin K5, hyperosmolarity and EDTA, but did not affect concanavalin A-stimulated xylose uptake. It is concluded that cycloheximide inhibits insulin-stimulated sugar transport at some late post-receptor step, and that this effect of cycloheximide is not secondary to the inhibition of protein synthesis.

Animals↗
PubMed1994

Effects of cycloheximide on the structural organization of the nucleolus and the coiled body in normal and stimulated supraoptic neurons of the rat.

This study was designed to determine the effects of cycloheximide, a protein synthesis inhibitor that interferes with rRNA synthesis and processing, on the nucleoli and coiled bodies of supraoptic nucleus neurons from normally-hydrated and osmotically-stimulated rats. The number of nucleoli and the nucleolar size were estimated on smear preparations of previously silver-impregnated supraoptic nucleus. No significant differences were registered in the mean number of nucleoli per cell in cycloheximide-treated rats. The number of nucleoli per neuron remained constant, at about 1.3, in all animal groups, suggesting that the nucleoli number is strictly regulated in differentiated neurons. By contrast, a significant reduction in the average nucleolar volume of supraoptic nucleus neurons was detected in cycloheximide-treated groups of rats in comparison with their equivalent non-treated groups. By electron microscopy, most nucleoli and coiled bodies of supraoptic nucleus neurons exhibited cycloheximide-induced alterations in their fine structure and configuration. Nucleolar changes included the occurrence of a few large fibrillar centres, the formation of microspherules and small intranucleolar vacuoles or dilated interstices, and the partial segregation of nucleolar components coupled with the transformation of reticulated nucleoli--a nucleolar configuration characteristic of supraoptic nucleus neurons of non-cycloheximide-treated rats--into compact ones. The redistribution of nucleolar components might reflect the interference with rDNA transcription, and also supports the hypothesis that the normal assembly of these components into the nucleolus depends upon ongoing nucleolar transcription. Concerning coiled bodies, most of them revealed ultrastructural alterations, particularly segregation of the amorphous matrix, compactation of coiled threads and formation of coiled body-derived dense bodies of fibrillar nature. Moreover, cycloheximide also induced the formation of smaller dense bodies--here referred to as dense microbodies--which presumably represent a distinct nuclear entity different from coiled bodies. Ultrastructural silver staining of nuclear bodies showed a selective silver reaction on the dense fibrillar component of normal and altered coiled bodies, as well as on the dense microbodies. The possible relationship between the nucleolus and both coiled bodies and dense microbodies is discussed.

Animals↗
PubMed1982

Ultrastructural effect of penicillin and cycloheximide on Chlamydia trachomatis strain HAR-13.

The effect of cycloheximide and penicillin on the ultrastructural morphology of C. trachomatis strain HAR-13 was examined by electron microscopy. HAR-13 infected McCoy cells were either treated with cycloheximide (1 microgram/ml) or cycloheximide (1 microgram/ml) plus penicillin G (100 U/ml). The studies revealed that cycloheximide alone induced no morphological alterations into the ultrastructure of HAR-13. Both HAR-13 developmental forms, the elementary body and reticulate body, were present inside the treated McCoy cells. The elementary bodies contained the central dense nucleoid and were about 0.3 microns in diameter, while the reticulate bodies were of typical gram negative bacterial morphology and were from 0.5-1.0 microns in diameter. Cycloheximide in combined treatment with pencillin produced giant, swollen reticulate bodies that were 2-4 microns in diameter and in some cases vacuolated. Elementary bodies were noticeably absent. These results indicate that cycloheximide does not alter the morphology of HAR-13. This system is a useful model for studying the ultrastructural morphology of C. trachomatis strain HAR-13.

Animals↗
PubMed1987

Pleiotropic changes in cycloheximide-resistant insect cell clones.

Somatic cell mutants resistant to drugs that interact with the eukaryotic ribosome provide a useful tool for studies on ribosome structure, function, and genetics. From Aedes albopictus (mosquito) cells, cycloheximide-resistant mutants (Cx-705 and Cx-738) that were about 30-fold more resistant to cycloheximide than the parental cells have been obtained. The observation that protein synthesis in cell-free lysates from Cx-705 and Cx-738 cells was resistant to cycloheximide led us to suspect that the alteration in these mutants might affect the ribosome. The present studies show that the cycloheximide-resistant cells grow poorly and eventually die at 34.5 degrees C, a temperature at which wild-type cells grow normally. Relative to control cells, the cycloheximide-resistant cells show increased sensitivity to G-418, another antibiotic that interacts with the eukaryotic ribosome. However, there were no differences between cycloheximide-resistant cells and wild-type cells in sensitivity to puromycin, emetine, or cryptopleurine. Cx-705 cells were predominantly diploid; in contrast, the frequency of tetraploid nuclei in Cx-738 cells was about 40%.

Aedes↗
PubMed1998

Isolation and characterisation of cycloheximide-sensitive mutants of Aspergillus nidulans.

Aspergillus nidulans is a non-pathogenic fungus with well-developed genetics which provides an excellent model system for studying different aspects of drug resistance in filamentous fungi. As a preliminary step to characterizing genes that confer pleiotropic drug resistance in Aspergillus, we isolated cycloheximide-sensitive mutants of A. nidulans, which is normally resistant to this drug. The rationale for this approach is to identify genes whose products are important for drug resistance by analysing mutations that alter the resistance/sensitivity status of the cell. Fifteen cycloheximide-sensitive (named scy for sensitive to cycloheximide) mutants of A. nidulans were isolated and genetically characterised. Each scy mutant was crossed with the wild-type strain and five of the crosses gave 50% cycloheximide-sensitive progeny suggesting that they carry a single mutation required for cycloheximide sensitivity. We examined ten scy mutants for resistance/sensitivity to other drugs or stress agents with different and/or the same mechanism of action. Six of these mutants exhibited other altered resistance/sensitivity phenotypes which were linked to the cycloheximide sensitivity. These six mutants were analyzed by pairwise crosses and found to represent six linkage groups, named scyA-F. One of the mutants showed fragmentation of its vacuolar system and, in addition, its growth was osmotic, low-pH, and oxidative-stress sensitive.

Aspergillus nidulans↗
PubMed2000

Effect of cycloheximide on tryptophan binding to rat hepatic nuclei.

This study evaluated whether cycloheximide, an inhibitor of protein synthesis, would affect the binding of L-tryptophan to rat hepatic nuclei or nuclear envelopes. Previous reports have indicated that the binding of L-tryptophan to hepatic nuclear envelope protein was saturable, stereospecific, and of high affinity. Also, the administration of L-tryptophan rapidly stimulated hepatic protein synthesis. In this study, we determined that the addition of cycloheximide in vitro inhibited 3H-tryptophan binding to hepatic nuclei or nuclear envelopes. Heat-treated cycloheximide failed to have this inhibitory binding effect. In vivo treatment of rats with cycloheximide diminished in vitro 3H-tryptophan binding to hepatic nuclei of treated rats compared to controls. Puromycin, another inhibitor of hepatic protein synthesis, when added in vitro did not affect 3H-tryptophan binding to hepatic nuclei but did diminish in vitro binding after in vivo treatment. Thus, cycloheximide added in vitro diminished 3H-tryptophan binding to hepatic nuclei probably by its structural effect on the receptor while cycloheximide administered in vivo may also act in part by inhibiting protein synthesis.

Amino Acids↗
PubMed1990

Divergent effects of cycloheximide on the induction of class II and class III cytochrome P450 mRNAs in cultures of adult rat hepatocytes.

We have previously reported that when hepatocytes isolated from adult male rats are cultured in serum-free medium on matrigel, a reconstituted basement membrane gel, it is possible to elicit a stimulation of gene expression for both Class II cytochrome P450b/e and Class III cytochrome P450p by phenobarbital treatment (E.G. Schuetz et al., 1990 J. Biol. Chem. 265, 1188-1192). In the present study, an investigation of the requirement of protein synthesis for the rise in mRNAs for these cytochromes, pretreatment of the cells with cycloheximide prior to adding phenobarbital or "phenobarbital-like" inducers to the culture medium inhibited induction of P450b/e mRNA (46-90%), whereas the accumulation of P450p mRNA was enhanced (2- to 19-fold). Heme depletion did not appear to explain these observations because the inhibitory effects of cycloheximide on the induction of P450b/e mRNA were not overcome by supplementation of the medium with exogenous heme or with delta-aminolevulinic acid. Because Class IIIA P450s are regulated by gender as well as by phenobarbital, we examined the basal expression of P450p mRNA in cultures of hepatocytes derived from male rats and found that cycloheximide treatment was without effect. However, in cultures of hepatocytes isolated from female rats, where P450p mRNA is barely detectable, cycloheximide treatment greatly enhanced expression of P450p mRNA. As was observed in the cultured cells, the treatment of living female rats with cycloheximide also increased the amounts of P450p mRNA to levels comparable to those found in livers of untreated male rats. Analysis of Northern blots hybridized with oligonucleotides specific for P450PCN1(IIIA1) and P450PCN2(IIIA2), respectively, revealed that untreated male rat liver and cultures of hepatocytes prepared from these animals expressed readily detectable amounts of P450PCN1(IIIA1) mRNA. Such analyses confirmed that cycloheximide treatment selectively increased P450PCN1(IIIA1) mRNA in female rat liver, whereas the amount of mRNA for P450PCN2(IIIA2), a closely related male-specific family member, was unaffected. We conclude that the pathways for the induction of P450b/e and P450p by phenobarbital, and the pathways for the gender-specific basal expression of P450PCN1(IIIA1) and P450PCN2(IIIA2) are not the same and can be distinguished by their differential response to inhibition of ongoing protein synthesis.

Animals↗
PubMed1990

Dermal fibroblasts from Down's syndrome patients share a cycloheximide-induced deficiency in collagen adhesion responses with normal aging cells.

Human skin fibroblasts from three different Down's syndrome patients (trisomy 21) of very different ages have been tested for their adhesion responses on tissue culture substrata coated with type I collagen, fibronectin (FN), and their combination after or during treatment of cells with cycloheximide to evaluate limitations in specific responses. It was shown previously that in vitro-aged papillary and reticular dermal fibroblasts from normal individuals do not generate F-actin stress fibers when pretreated with cycloheximide on collagen substrata but do so on FN substrata, a deficiency linked to limiting amounts/function of collagen-specific receptors in aging cells. In these studies, all three Down's fibroblast populations demonstrated a similar deficiency in stress fiber formation, evaluated by rhodamine-phalloidin staining, upon cycloheximide treatment at all passage levels. They remained competent for stress fiber formation on FN substrata and for reorganization of microtubule and intermediate filament networks on all substrata, demonstrating the specificity for the collagen matrix and for the F-actin cytoskeleton in this deficiency. The cycloheximide-induced deficiency could be readily reversed in all three cell populations by further incubation of cells in drug-free medium and, in some cases, by prior growth of cells in ascorbate-supplemented medium to stimulate collagen and possibly collagen receptor production. However, several pieces of evidence indicate that reduced amounts of FN and collagen synthesized by fibroblasts do not contribute to the cycloheximide-induced deficiency, including the inability to reverse the effect by treatment of cells with TGF beta. Several conclusions are suggested from these studies: (a) Down's dermal fibroblasts become deficient in collagen-specific receptor(s) upon cycloheximide treatment, which leads to altered transmembrane signaling and inability to reorganize F-actin into stress fibers; (b) Down's dermal fibroblasts at all passage levels have matrix adhesive phenotypes similar to those of aging fibroblasts from normal individuals; and (c) these studies provide further support for cells from Down's patients as a genetic model of aging in normal populations.

Actins↗
PubMed1989

Further analysis of lethal factors in cycloheximide-treated mice given low doses of bacterial lipopolysaccharide.

Endotoxin challenge (0.2 micrograms per mouse) 6 h after a standard dose of cycloheximide was compared with the previously-reported effects of simultaneous injection of cycloheximide and endotoxin. With the submicrogram dose of endotoxin given 6 h after cycloheximide, fatalities occurred without evidence of thrombogenic bilateral renal cortical necrosis which characterized mice dying after the two agents were given together. Anticoagulation with heparin or with ancrod is life-saving, indicating that cycloheximide-treated mice were fatally susceptible to fibrinogen-to-fibrin conversion, and that, in contrast to the situation where cycloheximide and endotoxin are given simultaneously, there was no essential demand for supplementary glycocorticosteroid. A dose of 5.0 micrograms of endotoxin given 6 h after cycloheximide was fatal; again no renal cortical necrosis occurred, but both ancrod and hydrocortisone were essential to ensure survival.

Ancrod↗
PubMed1986

Involvement of cycloheximide-sensitive mediators in the steroidogenic action of adrenocorticotropin and angiotensin II.

The involvement of short-lived proteins in the steroidogenic action of corticotropic peptides has been investigated in vitro by means of a perifusion technique using frog adrenal glands. Graded concentrations of cycloheximide (10(-7) M to 10(-5) M) led to a dose-related inhibition of corticosterone and aldosterone production. The perifusion model gives detailed information on the kinetics of the inhibitory effect of cycloheximide. This effect was rapidly observed (the lag period was about 15 min), maximum inhibition being obtained 25 min after the end of administration of the protein synthesis inhibitor. Whatever the concentration of cycloheximide, corticosteroid output returned to basal values 2 h after the onset of cycloheximide infusion. Stimulation of steroidogenesis by ACTH and angiotensin II was totally inhibited by cycloheximide (10(-6) M) indicating that the synthesis of a labile protein was required for the adrenal response to corticotropic peptides. In addition, the stimulatory effect of cAMP and PGE1, which are considered to be the second messengers of ACTH and angiotensin II in amphibian interrenal gland, was blocked by cycloheximide. Taken together, these data suggest that a labile protein is involved in an early step of corticosteroid biosynthesis in the frog.

Adrenal Cortex Hormones↗
PubMed1986

Depletion-replenishment of the testicular estrogen receptor: sensitivity to cycloheximide and actinomycin D.

Male rats (30-35 days old) were utilized to examine the process of depletion and replenishment of the testicular cytosolic estrogen receptor and to investigate the effects of cycloheximide and actinomycin D on these processes. The dose dependence and temporal nature of receptor depletion and replenishment were investigated. Maximum depletion (greater than 90%) occurred by 1 h after in vivo administration of either 5 or 10 micrograms estradiol-17 beta. Depletion of the cytosolic receptor at 1 h occurred concomitant to a marked increase in nuclear receptor thus indicating translocation. Receptor replenishment to control levels was observed by 6 h post treatment. To determine the requirements for transcriptional and translational events in the replenishment process, actinomycin D and cycloheximide were administered in vivo. Simultaneous treatment with cycloheximide and estradiol resulted in a significant inhibition of replenishment at 6 and 12 h post treatment of 46 and 60% below control levels, respectively. Cycloheximide treatment alone had no effect on receptor levels. A significant inhibition of replenishment at 6 h was also shown when cycloheximide was given 3 h after estradiol treatment. Cycloheximide administration at 6 h after estradiol significantly suppressed receptor levels at 12 h suggesting that replenished receptor levels at 6-12 h are in a state of rapid turnover. Receptor replenishment exhibited a different response to actinomycin D treatment in that significant inhibition was observed only when the drug was administered at 3 h after estradiol treatment. These results demonstrate that testicular cytosolic receptor depletion is dose and time dependent. The results further demonstrate that receptor replenishment involves protein synthesis and suggests that synthesis of new RNA might also be required.

Animals↗