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PubMed1976

Prompt elevation of rat serum alpha-fetoprotein by acute liver injury following a single injection of ethionine.

The mechanism of increased alpha-fetoprotein (AFP) production following a single injection of ethionine was investigated by using rats aged 5 weeks at the time of killing. Marked elevations of serum AFP concentrations occurred within 4 days in both male and female rats after administration of DL-ethionine or L-ethionine, although the increased levels of serum AFP and liver triglyceride in the adults were less marked in the male than in the female. No apparent necrosis of liver cells was observed in ethionine-treated rats. Frequent administrations of adenosine triphosphate after a single dose of ethionine prevented the increases in liver triglyceride and serum AFP levels. The increased concentrations of serum AFP, reaching a maximum level within 4 days, occurred before a slight increase in incorporation of 3H-thymidine into liver DNA. The serum AFP from ethionine-treated rats was immunologically and electrophoretically indistinguishable from that of fetal, carbontetrachloride-treated or hepatoma-bearing rats. These observations suggest that the increased production of AFP in ethionine-treated rats is closely associated with hepatic injury and is not the consequence of liver cell regeneration.

Adenosine Triphosphate↗
PubMed1976

Methionine metabolism in BHK cells: selection and characterization of ethionine resistant clones.

The selection of clones resistant to methionine antagonists was undertaken on baby hamster Kidney cells grown in a methionine free medium, supplemented with homocystine, folic acid and hydroxo-B12. Clones resistant to 30 mug/ml ethionine were isolated after mutagenesis at an induced mutation frequency of 2.3 X 10(-5). An ethionine resistant clone, ETH 304, was extensively studied. The resistant cells excreted methionine in the culture medium and the intracellular pools of methionine and SAM were two to five times greater in the resistant clone than in the wild type cells. A semidominant ethionine resistant phenotype was observed in hybrids between the wild type and this resistant clone. Measurement of the specific activity of menadione reductase, B12 methyltransferase and ATP: L-methionine S-adenosyl-transferase in crude extracts of the wild type showed a repressive action of methionine on the level of the three enzymes. However, the ethionine resistant clone ETH 304 was not modified in this function. Menadione reductase is feedback-inhibited by SAM in wild type cells. The enzyme of the ethionine resistant clone was significantly less sensitive to SAM. When a comparison of thermal stability was made between the wild type and ethionine resistant clone enzymes, it was found that the thermal stability of the latter was modified. Three other ethionine resistant clones, independantly isolated, were similarly affected in the properties of menadione reductase. These results suggest that the pathway of re-use of S-adenosyl homocysteine, produced during methylation reactions, is highly regulated by methionine and SAM.

5-Methyltetrahydrofolate-Homocysteine S-Methyltran↗
PubMed2003

Effect of IS-741 on ethionine-induced acute pancreatitis in rats: relation to pancreatic acinar cell regeneration.

BACKGROUND: Tissue destruction arising from neutrophil infiltration of the pancreas and other organs in acute pancreatitis is supposed to be suppressed by IS-741. We studied the effect of IS-741 on acute pancreatitis induced by DL-ethionine in rats. METHODS: Rats fed with a low protein diet for 11 days received daily intraperitoneal administration of DL-ethionine (20 mg/100 g) for the last 4 days of the diet. To evaluate the therapeutic effect on ethionine-induced pancreatitis, IS-741 (10 mg/kg s.c.) was administered every 8 h beginning after the second ethionine injection (IS group). An equal volume of saline was used for control rats as alternative to IS-741 (control group). The rats were killed 1, 3, 5, and 7 days after the last injection of ethionine. Blood was collected to measure concentrations of the inflammatory cytokine, interleukin-8. Histologic and biochemical examinations of the pancreas were performed. The pancreatic weight, DNA content, and protein levels were determined. The pancreas was histologically examined. RESULTS: Pancreatic tissue in the control group showed marked infiltration of inflammatory cells, and acinar cell necrosis was widespread 1 day after the last injection of ethionine (day 1). The severity of acute pancreatitis was alleviated in rats treated with IS-741 (IS group). Pancreatic wet weight and DNA content in the IS group were higher than those in the control group on day 1. Pancreatic protein level per DNA in the IS group was higher than that in the control group on day 7. The plasma interleukin-8 level in the control group was higher than that in the IS group on day 5. CONCLUSIONS: Therapeutic administration of IS-741 ameliorated ethionine-induced acute pancreatitis in rats, and IS-741 could be a useful drug to treat patients with severe acute pancreatitis.

Animals↗
PubMed1988

Ethionine-induced alterations of enzymes involved in lipid metabolism and their possible relationship to induction of fatty liver.

Changes of enzymes involved in the hepatic metabolism of long-chain fatty acids (palmitoyl-CoA synthetase (EC 6.2.1.3), carnitine palmitoyltransferase (EC 6.2.1.3), glycerophosphate acyltransferase (EC 2.3.1.15)) in the liver of male rats were examined after ethionine exposure. Ethionine administration resulted in a dose- and time-dependent enhancement of the palmitoyl-CoA synthetase activity both in the mitochondrial, peroxisomal and microsomal fractions. The total carnitine palmitoyltransferase activity in the mitochondrial fraction was enhanced. Ethionine administration was also associated with dose- and time-dependent changes of the microsomal glycerophosphate acyltransferase activity, whereas the mitochondrial enzyme activity was marginally affected. The hepatic triacylglycerol content of the ethionine-treated animals was increased. Hepatic lipids were accumulated in large droplets. Serum triacylglycerol and cholesterol were decreased. In particular, the serum HDL-cholesterol level was lowered. The concentration of ATP in the liver decreased. Accumulation of the metabolic product S-adenosylethionine (AdoEth) was observed for the first 2 days of exposure followed by a fall in S-adenosylmethionine (Ado-Met) during the next 10 days. Linear regression analysis of ATP content versus AdoEth and AdoMet showed highly significant correlations. A significant correlation between the hepatic triacylglycerol and AdoEth content was also observed upon ethionine treatment. The data show that ethionine perturbs the hepatic lipid metabolism. Enhanced esterification of long-chain fatty acids, but not a simple reduction of their oxidation, might contribute to ethionine-induced fatty liver in addition to a block in secretion of lipoproteins and decreased protein synthesis.

Acyltransferases↗
PubMed1968

Heaptic glutathione concentrations linked to ethionine toxicity in rats.

1. The effect of injected ethionine on liver GSH concentrations was studied in male and female rats. 2. Liver GSH concentrations were markedly and consistently decreased in 5hr. and elevated within 24-44hr. By 72hr. the amount of liver GSH of ethionine-poisoned rats had the same values as saline-injected control rats. At no time was erythrocyte GSH concentration affected by ethionine. 3. The concentrations of non-protein thiol compounds, glycogen and ATP were also significantly decreased when the rats were killed 5hr. after ethionine injection. 4. ATP, adenine or methionine did not prevent the decrease of liver GSH produced by ethionine. From these and other observations we conclude that ethionine is not an antagonist of methionine with respect to GSH metabolism. 5. The metabolic relationship between ethionine toxicity and liver GSH concentration is briefly discussed.

Adenine↗
PubMed1997

Protective effect of vitamin E against ethionine toxicity.

The effect of administration of ethionine on rat liver mitochondrial functions and the protective effect of vitamin E on ethionine induced damage was studied. Ethionine treatment decreased the rate of respiration, respiratory control ratio and P/O ratio. There was a significant decrease in the activities of NADH dehydrogenase, succinate cytochrome C reductase and cytochrome oxidase. A significant decrease was seen on membrane potential and on the levels of ATP. Among the mitochondrial phospholipids only cardiolipin decreased significantly. The lipid peroxide level increased significantly in ethionine treated rats. Administration of vitamin E prior to ethionine treatment relieved the effects (induced by ethionine) on all the parameters studied. This study shows that vitamin E protects against ethionine toxicity.

Adenine Nucleotides↗
PubMed1962

Restitution of pancreatic acinar cells following ethionine.

The regeneration of the pancreatic acinar cell was studied at four time periods after ethionine had destroyed most of the acinar cells. Within 2 days of the last ethionine injection, small basophilic cells (pre-acinar cells) with whorls of ergastoplasm or nebenkern were present. These cells also contained a decreased amount of Golgi substance, small zymogen granules, and a fine granularity of the nuclear matrix. They showed persistence of the characteristic ergastoplasm lesion produced by ethionine. Eight days after the last ethionine injection, the nebenkern was replaced by approximately normal appearing ergastoplasm and the nucleoli and Golgi bodies were enlarged. Zymogen granules were less dense but more abundant. Mitochondria were considerably enlarged. Most cells showed no ethionine lesions or only small foci of damage. Eighteen days after the cessation of ethionine, a good approximation of the normal acinar cell was present. The whorls of ergastoplasm appeared at a time (day 12) when basophilia was pronounced. Other studies showed that nucleic acid and protein precursors began to show an increased concentration in acinar cells at this time. The appearance of nebenkern during a phase of cellular recovery and its absence during a phase of replication when mitotic indices were high suggest that its presence is more indicative of ergastoplasmic synthesis than of cell multiplication as such. Possibly the increased density of zymogen granules was a reflection of this increased protein synthesis. The increase in size of Golgi apparatus occurred prior to the replenishment of zymogen granules and thus satisfied a precursor relationship for a possible role in the formation of these secretory structures. Evidence suggests that some injured acinar cells recover from the ethionine and protein-free regimen and give rise to most of the new acinar cells formed. It is possible that, under the severe conditions which prevailed, the centroacinar ductule cells may also have given rise to some acinar cells.

Acinar Cells↗
PubMed1979

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.

Amino Acyl-tRNA Synthetases↗
PubMed1975

Selective testicular lesions resulting from continuous prolonged intake of minimal amounts of ethionine.

A threshold dose of ethionine was determined which, when administered continuously for up to 10 months, produced testicular lesions in rats but did not interfere with body growth and did not produce histologic lesions in the pancreas. In the liver, only mild fatty changes were observed. Interstitial cells of the testis showed hyperplasia at three to four months, followed by dedifferentiation of these cells in the later stages of the experiment. Complete atrophy of tubules was seen in most segments, but even at 8 and 10 months of ethionine ingestion, well-defined segments revealed intact spermatogenesis in all animals. The hypothetical emergence of a mutant ethionine-resistant spermatogonial stem cell is discussed. When ethionine was withdrawn from the diet at 10 months, incomplete regeneration of tubular epithelium was seen two months later, but the interstitial cells remained of the nondifferentiated type. Fatty changes in the liver, comparable to those observed in male ethionine-treated animals only after castration, are likely to have resulted from dedifferentiation of Leydig cells with concomitant testosterone deficiency. Rats receiving smaller doses of ethionine showed fatty change in the liver although no testicular lesions were recognizable. It is possible that ethionine interfered with synthesis of testosterone before testicular lesions could be demonstrated by light microscopy.

Animals↗
PubMed1976

The metabolism of L-ethionine in rats fed alpha-naphthyl isothiocyanate.

L-[ethyl-2-14C] ethionine was administered in a single dose to rats fed a diet containing 0.10% alpha-naththyl isothiocyanate for a period of time between 6 and 99 days. Ethionine metabolites excreted into urine were investigated as a function of induced pathologic changes in the liver. A short-time exposure (6 and 14 days) to alpha-naththyl isothiocyanate increased the excretion of free ethionine and S-adenosylethionine at the expense of total ethionine sulfoxide. With the extended feeding period the excretion of total ethionine sulfoxide became normalized while the excretion of free ethionine and S-adenosylethionine decreased. The acetylated fraction of ethionine sulfoxide decreased rapidly and reached a minimum in 14 days of feeding. This fraction subsequently started to increase, but did not reach the values obtained in normal rats.

1-Naphthylisothiocyanate↗
PubMed1987

The synthesis of the adenosyl-moiety of S-adenosylethionine in liver of rats fed DL-ethionine.

The synthesis of the adenosyl-moiety of S-adenosylethionine from glycine was studied in normal rats and rats fed a diet containing 0.30% DL-ethionine for three weeks, using a L-ethionine probe. The liver of rats, pretreated by DL-ethionine feeding, incorporated--after injection of 20 mg L-ethionine/100 g body wt.--six times more C-14 from glycine-2-14C into the adenosyl-moiety of SAE than normal rats. Further increasing of doses up to 100 mg/100 g body wt. did not substantially change the incorporation in pre-exposed rats while in normal rats an almost complete inhibition of the incorporation was observed. The liver cells exposed to a chronic effect of DL-ethionine are able, after higher demands for ATP, to increase the ATP generation more effectively than normal cells. This adaptation to the toxic effect of ethionine represents one of the first alterations of the metabolic functions of liver parenchyme in the course of hepatic DL-ethionine cancerogenesis.

Adenosine↗
PubMed1984

Induction of hepatic heme oxygenase and its effect on drug metabolizing enzyme by DL-, D- and L-ethionine administration to rats.

The chronic administration of ethionine, an analogue of methionine and alkylating hepatocarcinogen, to rats resulted in the decrease of hepatic drug metabolizing enzyme activities and cytochrome P-450 content. In contrast, the activity of hepatic heme oxygenase, a first enzyme of heme degradative pathway, was increased following ethionine administration. delta-Aminolevulinic acid (ALA) synthetase, a key enzyme of heme biosynthesis pathway, was also increased except during 9 to 15 weeks of the experimental period. Changes of cytochrome P-450 content and heme oxygenase activity were proportional to the carcinogen provided period. Further, ethionine induced neoplastic nodules showed more profound changes in heme oxygenase, ALA synthetase and drug metabolizing enzyme activities than the surrounding liver. Similar changes in the enzyme activities were also obtained by a single administration of ethionine to rats and these effects were dependent upon dose levels of the carcinogen except ALA synthetase activity. These results revealed that ethionine is a mild inducer of hepatic heme oxygenase. It is thus likely that induction of heme oxygenase produced by ethionine could lead to the decrease of cytochrome P-450 and drug metabolizing enzyme activities in the liver. The decrease of heme availability due to induction of heme oxygenase by ethionine may be one of the explanations for the decrease of cytochrome P-450 content under the experimental conditions.

5-Aminolevulinate Synthetase↗
PubMed1981

The dose-related metabolism of L-ethionine in acute experiments with rats.

A method is described for a simple column chromatographic determination of N-acetylethionine, N-acetylethionine sulfoxide, and alpha-keto-gamma-ethiolbutyric acid on AG 1. With this analytical method and with chromatography on AG 50W, the urinary excretion pattern of ethionine, composed of all the aforementioned compounds, ethionine sulfoxide and S-adenosylethionine was studied in acute experiments in female rats as a function of the dose of L-[ethyl-1-14C]ethionine. Whereas N-acetylethionine sulfoxide is the major urinary metabolite at low ethionine doses, at higher doses increased amounts of unchanged ethionine and ethionine sulfoxide are found and account for the major portion of the administered dose at 460-613 mumol (75-100 mg)/100 g body wt. The urinary excretion pattern of S-adenosylethionine shows a close relationship to the concentration pattern of this metabolite in the kidney. The extent of t-RNA ethylation and the amount of carbon dioxide formed from the ethyl group of ethionine peak at doses of 77 (12.5) and 306 mumol (50 mg)/100 g body wt respectively, and do not increase further at higher doses.

Animals↗
PubMed1982

Metabolism of N-acetyl-L-ethionine sulfoxide in rats.

N-Acetyl-L-ethionine sulfoxide, the main urinary metabolic product of L-ethionine in rats, is produced and excreted by hepatocytes, as shown by its identification in liver extracts of rats administered L-ethionine and in the cultivation medium from primary culture of rat hepatocytes incubated with L-[ethyl-1-14C] ethionine. The metabolic fate of N-acetyl-L[ethyl-1-14C] ethionine isolated from the urine of rats injected with L-ethionine was examined in rats in vivo. This compound can be metabolized, to a small extent, into the usual metabolic products of L-ethionine: S-adenosylethionine and, to an increased extent to CO2.

Animals↗
PubMedDate not supplied

Methionine depletion modulates the antitumor and antimetastatic efficacy of ethionine.

The elevated methionine requirement for the growth of tumors, termed methionine dependence, is a potentially highly effective therapeutic target. To attack this target we are developing anti-methionine chemotherapy. In this study of anti-methionine chemotherapy we have observed that the methionine analog ethionine is synergistic with methionine depletion in arresting the growth of the Yoshida sarcoma both in vitro and when transplanted to nude mice. In contrast, ethionine in vitro in a methionine-containing medium is not effective against Yoshida sarcoma cells. Similarly, ethionine administered along with a methionine-containing diet is ineffective against the Yoshida sarcoma growing in nude mice. A methionine-depleted diet alone is only partially effective against tumor growth. The Yoshida sarcoma gave rise to metastases in 75% of the- organs observed in the mice on the methionine-containing diet, and 43 % of the organs in the mice on the methionine-free diet. In striking contrast, no metastases were observed in the ethionine-treated animals on the methionine-free diet. Anti-methionine chemotherapy consisting of dietary methionine depletion and ethionine administration caused an initial weight loss but the animals weight stabilized resulting in no animal deaths. The synergism of ethionine and methionine depletion is markedly similar in vitro and in vivo suggesting the observed efficacy is due to the specific anti-methionine targeting. Thus methionine depletion highly potentiates the anti-tumor and anti-metastatic effectiveness of ethionine suggesting that anti-methionine chemotherapy consisting of methionine depletion as a modulator of methionine analogs holds great promise as a new, tumor-selective therapeutic approach.

Animals↗
PubMed1976

Acute effects of ethionine stereoisomers on hepatic RNA and protein synthesis in swiss mice.

The acute biochemical effects of ethionine have been well studied in rats but not in mice. These results show that both hepatic RNA and protein synthesis in Swiss mice were inhibited by DL-ethionine. Protein synthesis was inhibited 30 to 40 percent 3 hr after 2500 mg/kg DL-ethionine while RNA synthesis was inhibited 80 to 90 percent 3 hr after 625 mg/kg DL-ethionine. Thus ethionine was a far more potent inhibitor of RNA synthesis than of protein synthesis. There was no sex difference in either of these responses. While both stereoisomers were active, the L isomer was a more potent inhibitor of RNA synthesis than was the D isomer. In male mice, 3 hr after 20 mg/kg L-ethionine, RNA synthesis was inhibited 80%, while after D-ethionine it was inhibited only 51%.

Animals↗
PubMed1977

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.

Animals↗
PubMed1990

Liver phosphatidylcholine hydroperoxidation provoked by ethionine-containing choline-deficient diet in mice.

It is shown that peroxidation of phosphatidylcholine (PC) is enhanced in liver of mice fed a hepatocarcinogenic choline-deficient diet containing 0.1% w/w ethionine. Mice were divided into 4 groups and fed for 4 weeks one of the following diets: choline-supplemented; choline-supplemented containing ethionine; choline-deficient; and choline-deficient containing ethionine. Phosphatidylcholine hydroperoxide (PCOOH) of liver lipids was measured by high performance liquid chromatography using a chemiluminescence detector. Mice fed a choline-deficient diet containing ethionine showed 6-fold higher PCOOH levels than the choline-supplemented control mice: the PCOOH/PC molar ratios of liver lipids were 32.3 X 10(-5) and 5.6 X 10(-5), respectively. In addition to this remarkable degree of lipid peroxidation in liver of mice fed the choline-deficient diet containing ethionine, we also observed a significant liver fatty infiltration, a decrease in plasma and liver alpha-tocopherol, and an increase in liver injury-indicative enzyme activities. Also, marker enzymes for hepatocarcinogenesis, glucose-6-phosphatase and gamma-glutamyl transpeptidase were affected. These data suggest that enhanced hydroperoxidation of phosphatidylcholine may participate in hepatocarcinogenesis provoked by choline deficiency in the presence of ethionine.

Animals↗