Effect Of Ethionine Research Articles

Folate-deficiency-induced homocysteinaemia in rats: disruption of S-adenosylmethionine's co-ordinate regulation of homocysteine metabolism.

In a recent hypothesis [Selhub and Miller (1992) Am. J. Clin. Nutr. 55, 131-138], we proposed that homocysteinaemia arises from an interruption in S-adenosylmethionine's (AdoMet) coordinate regulation of homocysteine metabolism. The present study was undertaken to test a prediction of this hypothesis, that homocysteinaemia due to folate deficiency results from impaired homocysteine remethylation due to the deficiency and impaired synthesis of AdoMet, with the consequent inability of this metabolite to function as an activator of homocysteine catabolism through cystathionine synthesis. Rats were made folate-deficient by feeding them with a folate-free amino-acid-defined diet supplemented with succinylsulphathiazole. After 4 weeks, the deficient rats exhibited a 9.8-fold higher mean plasma homocysteine concentration and a 3.2-fold lower mean hepatic AdoMet concentration compared with folate-replete controls. Subsequent supplementation for 3 weeks of the folate-deficient rats with increasing levels of folate in the diet resulted in graded decreases in plasma homocysteine levels, accompanied by graded increases in hepatic AdoMet levels. Thus plasma homocysteine and hepatic AdoMet concentrations were inversely correlated as folate status was modified. In a second experiment, the elevation of plasma homocysteine in the deficient rats was found to be reversible within 3 days by intraperitoneal injections of ethionine. This effect of ethionine is thought to be exerted through S-adenosylethionine, which is formed in the liver of these rats. Like AdoMet, S-adenosylethionine is an activator of cystathionine beta-synthase and will effectively promote the catabolism of homocysteine through cystathionine synthesis. In crude liver homogenates of the rats treated with ethionine, cystathionine beta-synthase activity was 3-fold higher than that measured in homogenates from vehicle-treated controls.

Generalizing the control process for embryonic genes

Embryonic genes are considered as a separate subset of genes with unique chromatin properties. There is a problem of defining the duration of perturbations of embryonic gene activity that has been chemically induced and the normal relatively longer lasting changes that occur during differentiation. This problem may be related to unique properties of the chromatin of embryonic genes. Methylation of DNA is thought to be only one level of control and the superstructure of chromatin involving heterochromatin is of equal importance to embryonic gene expression. Proto-oncogenes are considered to be embryonic type genes whose activities are regulated under the same mechanisms by which other embryonic genes are regulated. Control aspects are discussed in the light of i) repressor-derepressor and blocking-deblocking mechanisms, ii) activator genes, pseudogenes, LINES, SINES, v-type position effects, iii) effects of ethionine, and iv) steroid hormone effects especially with respect to a subset of repeated rRNA genes which are considered to be structured in embryonic type chromatin.

Biochemical and developmental features of experimental phenylketonuria induced by L-ethionine in suckling rats.

Suckling rats were injected subcutaneously with doses of L-ethionine (0.1 mumole/g body wt) at intervals of 12 hr. In the latter group, phenylalanine hydroxylase was effectively inhibited in vivo resulting in hyperphenylalaninemia and phenylketonuria. Due to the well-known sex-specific differences in L-ethionine metabolism female rats were much more affected by chronic administration of L-ethionine. The underlying mechanism of enzyme inhibition by ethionine could be disturbed protein synthesis and impaired protein phosphorylation, which was suggested by pronounced decreases in ATP content in liver. In the high dosage group depletions mainly of the branched-chain amino acids and lysine occurred in serum and brain, whereas the concentrations of methionine and tryptophan were increased. Tyrosine tended to be decreased in the course of hyperphenylalaninemia. Hyperphenylalaninemia and other resulting amino acid imbalances obviously impaired brain development during the early postnatal period. Concomitantly with reductions in protein concentrations, the activity of cathepsin D, a major intralysosomal acid proteinase, was increased in brain, suggesting also higher protein catabolism in brain. Side effects of this treatment, however, were higher mortality, loss of body weight, and a general impression of delayed development, resembling a state of undernutrition to some extent. These obvious side effects of ethionine limit the usefulness of ethionine as a suitable model for classic phenylketonuria in suckling rats.

Einfluß von D,L‐Ethionin auf Zellkulturen von Ruta graveolens L

AbstractD,L‐Ethionine was added in varying concentrations (0.1–1 mM) to two cell suspension cultures of Ruta graveolens. Growth, alkaloid formation and activities of some shikimate pathway‐specific enzymes in these cultures were estimated. Also the effect of ethionine on shikimate pathwayspecific enzymes under in vitro conditions was followed. Growth is only slightly inhibited in supplemented cultures. Alkaloid formation is drastically reduced in a low‐producing and to a lesser extent in the high producing cell line by ethionine. Activities of DAHP synthase, chorismate mutase, and anthranilate synthase in the presence of ethionine are in different Ruta strains to a varying degree affected.

Effect of ethionine on the in vitro synthesis and degradation of mitochondrial translation products in yeast

The effect of ethionine, an amino acid analog of methionine, has been studied in Saccharomyces cerevisiae in relation to cell growth, oxygen consumption, in vitro protein synthesis of mitochondrial translation products (MTPs) and the degradation of those mitoribosomally made proteins by an ATP-dependent process present within the organelle. Ethionine was found to increase the generation time of those cells already committed to cell division and to abolish the initiation of new cell cycles. Oxygen consumption of cultures grown in the presence of the analog was drastically reduced. Ethionine was also found to impair the incorporation of methionine and leucine into mitochondrial translation products, however the synthesis of proteins was not totally blocked and, apparently, mitochondria utilized ethionine as a precursor amino acid. MTPs synthesized by isolated mitochondria in the presence of ethionine were rapidly degraded inside the organelle at a faster rate compared with the normal proteins synthesized under identical conditions in the mitochondria. It is also shown that these in vitro synthesized proteins are degraded by an ATP-stimulated proteolytic system, as has been previously established.

Effect of ethionine on synthesis and methylation of ribosomal ribonucleic acid in regenerating rat liver

Ethionine, a hepatocarcinogen, was administered into rats 24 h before partial hepatectomy and immediately thereafter. Hepatic precursor ribosomal RNA (pre-rRNA) obtained 20 h after the operation of rats injected with ethionine and adenine resulted in methyl deficiency as judged by the incorporation of [ 3H]methyl group of S-adenosylmethionine into nuclear rRNA by partially purified rRNA methylase. The ethionine and adenine treatment causes methyl deficiency of nuclear rRNA at 2′-hydroxyribose sites of cytidine and uridine, but not at base sites. Although the ethionine and adenine treatment produced no significant change in total hepatic RNA synthesis in vivo assayed by the incorporation of labeled orotate, a one-third increase in nuclear rRNA synthesis as well as a one-third decrease in microsomal rRNA synthesis was found under the treatment. These results suggest that the undermethylation at 2′-hydroxyribose of pre-rRNA in liver nucleus, which is caused by ethionine and adenine administration into rats, causes an inhibition of the processing of nuclear pre-rRNA to cytoplasmic rRNA.

Ethionine-Induced alterations of tRNA metabolism.

Ethionine, the ethyl analog of methionine, is a hepatoearcinogen when administered chronically in the diet to rats (Farber 1963). Studies with radioactive ethionine revealed that tRNA was the most extensively labeled nucleic acid species after ethionine administration (Farber et al. 1967). Further studies in recent years have led to extremely interesting findings concerning the effect of ethionine on tRNA metabolism.

Effects of ethionine on the replicational fidelity in V79 Chinese hamster cells

The possibility that ethione, the ethyl analog of methionine and potent liver carcinogen, exerts its action by blocking the methylation of DNA and thereby rendering the post-replictive methylation instructed error-avoidance system inoperative was investigated. While the results are not directly supportive for the existence of such a repair system in V79 Chinese hamster cells, effects of ethionine were found. Following the exposure of ethionine-treated cells to EMS an increase in the cell killing and an decrease in mutation induction was observed. The base analog, 6-hydroxyaminopurine, was shown to be clearly mutagenic in the mammalian cells and in the presence of ethionine a drastic decrease in mutant frequency was observed. Ethionine itself did not appear mutagenic over the entire dose range tested (1–1000 μg/ml).

The mode of action of ethionine foliar sprays against potato common scab ( Streptomyces scabies)

Foliar sprays of ethionine lower the incidence of potato common scab. Evidence given here indicates that this is associated with one or all of the following effects (i) the pathogen ( Streptomyces scabies ) readily accumulating ethionine from the tubers, (ii) faster metabolism of ethionine in S. scabies than in the tuber and (iii) disruption of methionine metabolism by ethionine in S. scabies . In culture this disruption was alleviated by methionine and by its biosynthetic precursors. Ethionine decreased the absorbtion of L -[U- 14 C]homoserine, L -[4,5- 3 H]Iysine and L -[ 35 S]methionine, but only altered the metabolism of homoserine and methionine. No effect of ethionine on methionine metabolism was detected in potato tubers.

Effects of ethionine on digestive enzyme synthesis and discharge by mouse pancreas.

The earliest changes noted during the evolution of pancreatitis induced by feeding mice a choline-deficient ethionine-supplemented (CDE) diet are an increase in the number of zymogen granules in pancreatic acinar cells and an increase in digestive enzyme content of the pancreas. We have studied the processes of protein and digestive enzyme synthesis and discharge at varying times after institution of the CDE diet, a choline-deficient diet (CD), and a diet containing ethionine but not choline-deficient (E). Both the CDE and E diets increased digestive enzyme content within 12 h of their institution. Both the CDE and E diets reduced the rate of protein and amylase synthesis and caused a marked reduction in the rate of protein and amylase discharge from the pancreas. These changes were greatest and were noted earliest in the CDE diet group. A marked reduction in secretagogue-induced in vivo and in vitro amylase discharge followed ingestion of either the CDE or E diet. These studies indicate that the increased pancreatic content of digestive enzymes noted after ingestion of the CDE and E diets results from an ethionine-induced decrease in the rat of digestive enzyme discharge. This phenomenon is enhanced by simultaneous choline deficiency. Subsequent intrapancreatic activation of zymogens may couple these changes in enzyme content to the development of hemorrhagic pancreatitis.

Effects of ethionine on tRNA methylation in male and female rats

Administration of hepatocarcinogens to rats results in an increase in tRNA methyltransferase activity in the target tissues. Ethionine is active as a carcinogen only in female rats and only in females is this increase in enzyme activity seen. However, ethionine also causes the formation of methyl-deficient tRNA in the liver. Other hepatocarcinogens do not do this. Ethionine is equally effective in this action in males and females. Thus, the two actions of ethionine are completely separable, and the methyl-deficiency of tRNA is caused by an activity not identical with the carcinogenic one.

Functionally impaired tRNA from ethionine treated rats as detected in injected Xenopus oocytes

Treatment of rats with ethionine was found to cause severe impairment in the aminoacylation capacity of tRNA. This effect was only observed when assayed in injected oocytes, while invitro assays of aminoacylation failed to detect differences between normal tRNA and tRNA from ethionine treated animals. The effect of ethionine on the tRNA population was not uniform and differed for various amino acid specific tRNAs. Thus liver tRNA from ethionine treated rats showed a decreased capacity for phenylalanine aminoacylation, while no change was found in the case of leucine. On the other hand, the level of histidine aminoacylation was higher for tRNA from ethionine treated animals. An even more complex response was observed with methionine aminoacylation where tRNA from ethionine treated animals showed an initially faster rate than control tRNA. With more prolonged incubation periods, the methionyl-tRNA from ethionine treated animals was deacylated at an accelerated rate while the level of normal methionyl-tRNA remained almost constant. In addition to the aminoacylation reaction, the participation of aminoacyl-tRNA in protein synthesis was severely impaired. In this case, both the injected oocyte system and the cell-free wheat germ assay revealed these differences which were manifested with various mRNA and viral RNA preparations.

Effect of ethionine on gamma-cystathionase, homoserine dehydratase and cysteine desulfhydrase activities.

The administration of ethionine results in a rapid and marked increase in rat liver cysteine desulfhydrase activity. However, this antimetabolite of methionine does not affect the hepatic levels of homoserine dehydratase and gamma-cystathionase.

Effect of ethionine on the polypeptide composition of rat liver nuclear envelope [proceedings

Effect of ethionine on the polypeptide composition of rat liver nuclear envelope [proceedings

Effect of ethionine on the rough endoplasmic reticulum from male and female rat liver.

Ethionine causes a decrease in the amount of rough endoplasmic reticulum in rat liver, the effect being greater in female than in male rats. Rough endoplasmic reticulum isolated from rat liver 24 hr after ethionine injection and stripped of its ribosomes partially lost its in vitro ribosome binding capacity. However, no differences were detected between the binding affinities of ribosomes, isolated from either untreated animals or intoxicated rats, to stripped rough membranes derived from normal rats. Structural changes occur in the rough endoplasmic reticulum of the ethionine treated rats, while the ribosomes are still bound to the membrane.

Effects of ethionine and phenobarbital on the phosphatidylcholines of rat liver.

The diglyceride species of phosphatidylcholines from livers of male rats after treatment of the animals with ethionine (1 mg/g divided among 4 doses 2 hr apart), phenobarbital (80 mg/kg each day for 3 days), or a combination of the two drugs were determined using gas chromatography. Ethionine treatment greatly elevated the diene species (significant at the 0.005 level for 34:2 and 0.001 level for 36:2). Phenobarbital treatment had no significant effect on the quantity of 34:2 but slightly increased that of 36:2 (significant at the 0.05 level). Both drugs caused relative decreases in the quantities of 38:4 (significant at the 0.001 level for ethionine and at the 0.01 level for phenobarbital). Ethionine decreased the content of 36:4 (significant at the 0.01 level) while phenobarbital treatment did not produce a significant effect on this fraction. Thus, while ethionine produced marked effects on the quantities of the various molecular species, the effects of phenobarbital were less dramatic. Combined treatment with both drugs generally produced levels of species similar to those produced by ethionine alone.

The carcinogen ethionine elevates progesterone levels.

ETHIONINE is a potent carcinogen, but little is known about its mode of action. It is known that it does not react extensively with DNA1. It may be an ubiquitous carcinogen, as it is synthesised by Escherichia coli2 and several other microorganisms, so studies of its mode of action are important. We reported recently a novel effect of ethionine in the immature chick3. The oviducts of chicks previously stimulated with oestrogen behaved after the administration of ethionine as if they had received a second stimulation with oestrogen or progestin4–6. The egg white proteins, ovalbumin and conalbumin were synthesised and distinct morphological changes, characteristic of stimulation by oestrogen or progestin appeared. It was thus not clear whether ethionine (or its metabolic product) was affecting steroid hormone receptors7 directly, or interferring in some way with steroid hormone metabolism to produce elevated levels of endogenous oestrogen or progestin. We report here that ethionine or its sulphoxide are unique in inducing in the chick oviduct the effects cited above; analogues were inactive. We also report that the administration of ethionine elevates serum progesterone levels over 10-fold, to a concentration which may be sufficient to account for the profound changes in the immature oviduct.

Alterations of tRNA modification in mammalian systems: the effect of ethionine

The relationship between the modification of tRNA and its ability to act as a substrate for homologous tRNA modification enzymes in vitro was studied. The tRNA extracted from the livers of rats was active as a substrate for in vitro methylation with extracts from normal rat liver 19 h after treatment with L-ethionine (35 mg/100 g/24 h). After 4 weeks of feeding a diet containing o.25% DL-ethionine, the tRNA was a poor substrate for methylation in vitro, even though it was deficient in methylated nucleosides. Only 18% and 7% of the available sites could be methylated after 67 h and 4 weeks, respectively, of ethionine treatment. 3-(3-amino-3-carboxypropyl)uridine, a nucleoside that is also synthesized from S-adenosylmethionine, was assayed in individual tRNAs by their reactivity with the N-hydroxysuccinimide ester of phenoxyacetic acid. The reactivity of tRNAIle, tRNAAsn, and tRNAThr was decreased by treatment with ethionine at 67 h as well as at 2 and 4 weeks, although no difference could be detected at 19 h.

The effect of ethionine on ribonucleic acid synthesis in rat liver.

1. By 1h after administration of ethionine to the female rat the appearance of newly synthesized 18SrRNA in the cytoplasm is completely inhibited. This is not caused by inhibition of RNA synthesis, for the synthesis of the large ribosomal precursor RNA (45S) and of tRNA continues. Cleavage of 45S RNA to 32S RNA also occurs, but there was no evidence for the accumulation of mature or immature rRNA in the nucleus. 2. The effect of ethionine on the maturation of rRNA was not mimicked by an inhibitor of protein synthesis (cycloheximide) or an inhibitor of polyamine synthesis [methylglyoxal bis(guanylhydrazone)]. 3. Unlike the ethionine-induced inhibition of protein synthesis, this effect was not prevented by concurrent administration of inosine. A similar effect could be induced in HeLa cells by incubation for 1h in a medium lacking methionine. The ATP concentration in these cells was normal. From these two observations it was concluded that the effect of etionine on rRNA maturation is not caused by an ethionine-induced lack of ATP. It is suggested that ethionine, by lowering the hepatic concentration of S-adenosylmethionine, prevents methylation of the ribosomal precursor. The methylation is essential for the correct maturation of the molecule; without methylation complete degradation occurs.

The Effect of Ethionine on Triglyceride Synthesis in Rat Liver

Conference Article| March 01 1973 The Effect of Ethionine on Triglyceride Synthesis in Rat Liver MILAN VAVREĈKA MILAN VAVREĈKA 1British Industrial Biological Research Association, Woodmasterne Road, Carshalton, Surrey, U.K. Search for other works by this author on: This Site PubMed Google Scholar Biochem Soc Trans (1973) 1 (2): 438–440. https://doi.org/10.1042/bst0010438 Views Icon Views Article contents Figures & tables Video Audio Supplementary Data Peer Review Share Icon Share Twitter LinkedIn Cite Icon Cite Get Permissions Citation MILAN VAVREĈKA; The Effect of Ethionine on Triglyceride Synthesis in Rat Liver. Biochem Soc Trans 1 March 1973; 1 (2): 438–440. doi: https://doi.org/10.1042/bst0010438 Download citation file: Ris (Zotero) Reference Manager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbar search Search Dropdown Menu toolbar search search input Search input auto suggest filter your search All ContentAll JournalsBiochemical Society Transactions Search Advanced Search This content is only available as a PDF. © 1973 Biochemical Society1973 Article PDF first page preview Close Modal You do not currently have access to this content.