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PubMed1983

The influence of ethionine-supplemented soy protein diet on cell-mediated and humoral immunity.

These studies were designed to investigate the influence of ethionine, a suspected carcinogen, on cell-mediated (CMI) and humoral immunity. It is believed that ethionine, an analog of methionine which is produced by intestinal bacteria, could have significant relevance to health. To study the effect of ethionine on immune responsiveness, three groups of mice were allowed to feed ad libitum for 5 weeks on one of the following regimens: diet 1, a basal diet of 16% soy protein; diet 2, soy protein supplemented with 0.6% dl-methionine; and diet 3, soy protein supplemented with 0.1% dl-ethionine. The immunological parameters measured were responsiveness to mitogens, [phytohemagglutinin (PHA), concanavalin A (Con A), pokeweed mitogen (PWM), and lipopolysaccharide (LPS)], delayed-type hypersensitivity (DTH) to dinitrofluorobenzene (DNFB), and antibody formation to sheep red blood cells (SRBC). There were no significant differences in mitogen and antigen responses in mice maintained on diets 1 and 2 as measured by thymidine uptake in proliferating lymphocytes. However, there was a significant suppression in mitogen responsiveness in mice that received diet 3. DTH was also suppressed in mice on diet 3. Antibody levels were similar in all groups. Thus, there was clear evidence of suppression of CMI by ethionine in these studies.

Animals↗
PubMed1983

Threonine production by ethionine-resistant mutants of Serratia marcescens.

Ethionine reduced both the growth rate and the final growth level of Serratia marcescens Sr41. Growth inhibition was completely reversed by methionine. Strain D-315, defective in homoserine dehydrogenase I, was more sensitive to ethionine-mediated growth inhibition than was the wild-type strain. Ethionine-resistant mutants were isolated from cultures of strain D-316, which was derived from strain D-315 as a threonine deaminase-deficient mutant. Of 60 resistant colonies, 7 excreted threonine on minimal agar plates. One threonine-excreting strain, ETr17, was highly resistant to ethionine and, moreover, insensitive to methionine-mediated growth inhibition, whereas the parent strain was sensitive. When cultured in minimal medium with or without excess methionine, strain ETr17 had a higher homoserine dehydrogenase level than did strain D-316. The homoserine dehydrogenase activity was not inhibited by threonine or methionine. Transductional analysis revealed that the ethionine-resistant (etr-1) mutation carried by strain ETr17 was located in the metBM-argE region and caused the derepressed synthesis of homoserine dehydrogenase II. Strain ETr17 had a higher aspartokinase level than did the parent strain. By transductional cross with the argE+ marker, the etr-1 mutation was transferred into strain D-562 which was derived from D-505, a strain defective in aspartokinases I and III. The constructed strain had a higher aspartokinase level than did strain D-505 in medium with or without excess methionine, indicating that the etr-1 mutation led to the derepressed synthesis of aspartokinase II. Strain ETr17 produced about 8 mg of threonine per ml of medium containing sucrose and urea.

Chromosome Mapping↗
PubMed1971

Porphyrin overproduction by Pseudomonas denitrificans: essentiality of betaine and stimulation by ethionine.

Ethionine supplementation of a defined medium for growth of Pseudomonas denitrificans inhibited vitamin B(12) overproduction and led to the elaboration of a red pigment. The pigment was shown to be coproporphyrin III. Inhibition by ethionine of cobalamin synthesis is probably due to interference of methylation of the corrin nucleus by methionine. Accumulation of coproporphyrin III is thought to result from interference by ethionine with the activity of methionine in the coproporphyrinogenase reaction; this would inhibit formation of heme, the feedback inhibitor and corepressor of delta-aminolevulinate synthetase, thus allowing unregulated synthesis of coproporphyrinogen III and its degradation product, coproporphyrin III. Betaine, known to be required for vitamin B12 overproduction, was found to be an essential requirement for porphyrin overproduction in the presence of ethionine. Low-level production of porphyrin, which occurs in the absence of ethionine, also required betaine supplementation. Betaine is thus required for overproduction of both corrins and porphyrins in P. denitrificans.

Absorption↗
PubMed1980

Polymethylpolysaccharide synthesis in an ethionine-resistant mutant of Mycobacterium smegmatis.

Mutants of Mycobacterium smegmatis were selected for resistance to ethionine in an effort to obtain methylation-defective strains that were altered in their ability to make methylmannose polysaccharides (MMP) or methylglucose lipopolysaccharides. Two methods were developed for the detection of MMP in cell extracts to aid in the screening for potential mutants, one a qualitative procedure based on iodine binding by the sample after paper chromatography and the other a quantitative procedure based on fluorimetric titration of the MMP with parinaric acid. An ethionine-resistant mutant was obtained that contained only about 25% of the normal level of S-adenosylmethionine and 10% of the normal level of methionine adenosyltransferase (adenosine 5'-triphosphate:L-methionine S-adenosyltransferase, EC 2.5.1.6) activity. When grown in the presence of 0.1% ethionine, the mutant cells contained about 50% of the wild-type levels of methylglucose lipopolysaccharides but only about 7% of the normal level of MMP (wild-type cells contain about 0.14 mM MMP and the mutant contains about 0.01 mM MMP). The amount of fatty acid synthesis in the ethionine-resistant mutant grown in the presence of ethionine was not dramatically altered although the mutant accumulated more short-chain and less long-chain unsaturated fatty acids than the wild-type cells.

Drug Resistance, Microbial↗
PubMed1982

Altered insulin and glucagon secretion in perfused ethionine-treated rat pancreases.

The endocrine secretory function of rat pancreases in which pancreatitis had been induced by feeding rats a 0.5% ethionine diet was investigated. Despite loss of 50% of exocrine tissue and widespread destruction of acinar structure, pancreatic insulin and glucagon contents and 4-h fasting plasma insulin levels in vivo did not differ significantly from those of food-restricted, weight-matched controls. Plasma glucose concentrations (fasting and after oral glucose) were significantly lower than control. In isolated, perfused ethionine-treated pancreases secretin failed to stimulate insulin secretion, whereas basal insulin secretion and insulin responses to glucose, arginine, gastric inhibitory polypeptide, vasoactive intestinal peptide (VIP), and somatostatin were similar to those of controls. Basal glucagon secretion was elevated in ethionine-treated pancreases, and glucagon outputs in response to arginine, VIP, and somatostatin showed a consistent trend toward higher levels than those of controls. These findings demonstrate that ethionine-induced pancreatitis selectively impairs islet secretory function. These effects may be due to damage to islet cell membranes by exocrine enzymes and/or a direct pathogenic action of ethionine on the islets.

Animals↗
PubMed1969

Effect of DL-ethionine on the intestinal absorption and transport of palmitic acid-1-14C and tripalmitin-14C. Role of intramucosal factors in the uptake of luminal lipids.

The effect of DL-ethionine on the uptake and transport of lipid by the rat small intestine was investigated. A cottonseed oil emulsion containing (14)C-labeled tripalmitin or palmitic acid was administered intragastrically to rats pretreated with DL-ethionine, DL-ethionine plus methionine, or saline, and the rats were sacrificed 2, 4, and 6 hr later. Lipids from the plasma, the stomach, the colon, the luminal contents of the small intestine, and the wall of the small intestine were extracted, fractionated, and their radioactivity assayed. Ethionine markedly inhibited the uptake of lipids by the small intestine. This inhibition was not related to impairment of intraluminal lipolysis since analagous inhibitions were observed when palmitic acid or predigested triglyceride (TG), obtained through a jejunal fistula from normal animals, was administered instead of tripalmitin. Ethionine also inhibited the transport of lipid from the wall of the small intestine. A significant fraction of the administered lipid remained in the wall of the small intestine, and only a small fraction was transported to the blood stream. Although most of the wall radioactivity was in the form of TG, significant proportions were also found in the free fatty acid (FFA) and partial glyceride fractions, indicating a marked inhibition of mucosal reesterification to TG. The degree of inhibition of mucosal reesterification and the degree of inhibition of transport of wall lipids were directly related to the degree of inhibition of uptake of luminal radioactivity. This relationship suggests that the rate of reesterification, the level of mucosal FFA, and the rate of transport of intramucosal TG may be of importance in determining the extent of uptake of intraluminal lipid by the mucosal cells. Since a significant fraction of the wall radioactivity was in the form of TG, the decreased transport of wall lipids was attributed to an impairment of chylomicron completion due to inhibition of either the synthesis of chylomicron apoprotein or the association of preformed TG with the protein moiety of chylomicrons. Experiments with labeled amino acids support the first possibility.

Animals↗
PubMed1986

Rapid changes in glucose metabolism following the administration of ethionine: its role in regulating hepatic protein synthesis.

The relationship between the changes in portal glucagon, insulin, glucose, and hepatic protein synthesis were investigated during ethionine intoxication. There was a 50% decrease in blood glucose, a seven-fold increase in portal glucagon and a 90% increase in portal insulin, all of which coincided temporally with the inhibition of hepatic protein synthesis. When reversal of ethionine intoxication was initiated with adenine it simultaneously restored blood glucose, insulin, glucagon, and protein synthesis. Protein synthesis could not be adequately restored by glucose, but in this case hepatic ATP levels did not increase. In addition, glucose given by stomach tube prior to ethionine did not prevent the action of ethionine, though it did maintain plasma glucose levels and prevented the decrease in plasma insulin and increase in plasma glucagon. These results show that in vivo regulation of hepatic protein synthesis during ethionine intoxication is not likely to be mediated by portal insulin, glucose, and glucagon.

Adenine↗
PubMed1975

Acute hemorrhagic pancreatic necrosis in mice. Influence of the age and sex of the animals and of dietary ethionine, choline, methionine, and adenine sulfate.

The influence of several factors on the development of acute hemorrhagic pancreatitis (pancreatic necrosis) with fat necrosis in mice fed DL-ethionine with a choline-deficient diet has been investigated. The results showed that: a) the incidence of the induced disease is dependent upon the age and sex of the animals and the dietary level of ethionine; b) 100% of young female mice fed 0.5% ethionine develop acute hemorrhagic pancreatitis and die within 5 days; c) the incidence is only 10 to 20% when 0.5% ethionine is fed with either a choline-supplemented diet or with laboratory chow; and d) development of pancreatic pathology is completely prevented by the inclusion in the diet of 0.5% methionine but not by the inclusion of 0.5% adenine. Possible mechanisms whereby choline deficiency potentiates the pancreatotoxicity of ethionine in mice are discussed.

Acute Disease↗
PubMed1990

Regulation of cholesterol metabolism in the ethionine-induced premalignant rat liver.

The early premalignant liver provides a model in which to study metabolic alterations that may be permissive for the development of full malignancy. Although there are biochemical changes in this model, there are no detectable morphological ones when compared with a normal, fully differentiated liver. The maintenance of cholesterol homeostasis, essential for proper functioning of mammalian cells, is known to be altered in malignancy. We used the ethionine-induced premalignant liver model to study the effects of the premalignant state on cellular parameters involved in the maintenance of hepatic cholesterol homeostasis. Cholesterol synthesis was elevated about twofold in the livers of rats treated with ethionine as was the activity of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, its rate limiting enzyme. There was no change in reductase activation state. Acyl coenzyme A:cholesterol acyl-transferase (ACAT) was decreased about 30%, and cholesterol 7 alpha-hydroxylase, about 50%. There was no significant change in neutral cholesteryl ester hydrolase activity, but acid hydrolase activity was decreased. There was little change in low density lipoprotein receptor protein as determined by immunoblotting. Biliary lipid secretion was in the normal range when expressed per gram liver; however, bile flow was doubled. The ethionine-fed animals were mildly hypocholesterolemic and had an altered serum lipoprotein pattern. Cholesterol synthesis and HMG-CoA reductase activity exhibited decreased sensitivities to inhibition by dietary cholesterol when compared to control livers. However, sensitivity to intragastrically administered mevalonolactone was not altered. Although ACAT activity was increased by mevalonolactone administration to levels similar to those in untreated animals, it was not increased in the ethionine-fed animals by feeding cholesterol. The ethionine-induced premalignant liver responded to ethinyl estradiol treatment in a manner similar to that of the control, i.e., profound hypolipidemia, increased low density lipoprotein receptors, decreased reductase activity, and increased cholesterol esterification. Thus, these livers retained their estrogen responsiveness. Taken together, the data demonstrate that the major elements involved in maintaining hepatic cholesterol homeostasis are present in the premalignant liver, although in some cases at levels that are different from the control. However, the susceptibility to regulation was altered in these livers to suggest markedly decreased availability of cholesterol of exogenous origin to the regulatory compartment(s). Further, coupling of the different elements involved in maintenance of hepatic cholesterol homeostasis appeared to have been changed.

Animals↗
PubMed1978

Enhancement of DL-ethionine-induced liver carcinogenesis in rats fed a choline-devoid diet.

The effects of a choline-devoid (CD) or a choline-supplemented (CS) diet on the induction of liver tumors in rats by DL-ethionine were investigated. Groups of male outbred Sprague-Dawley rats were fed a plain CD or a plain CS diet, or the same diets containing 0.05% DL-ethionine. Hepatocellular carcinomas developed in 50% of the rats fed the CD+ethionine diet for 14 weeks and in about 80% of the rats fed the same diet for 22-30 weeks. No hepatocellular carcinomas developed in rats fed the CS+ethionine diet, the plain CD diet, or the plain CS diet up to 30 weeks. The findings suggest that a CD diet alters the response of rat liver to DL-ethionine and leads to an early and enhanced induction of hepatocellular carcinoma.

Animals↗
PubMed1978

[Activity of parotid isoamylases in the ethionine-treated rat (author's transl)].

In order to investigate the effects of ethionine (an antagonist of the essential amino acid, methionine) on the enzyme synthesis in the rat-parotid gland, rats were fed methionine-deficient diet and treated with DL-ethionine for 4 and 10 days. Compared with the controls, not only the synthesis but also the secretion of parotid isoamylases was impaired by ethionine. Acinar isoamylase activities dropped initially but increased distinctly after 10 days of ethionine treatment, possibly due to intra- as well as extracellular impairment of acinar protein secretion. After another 10 days during which no ethionine was given, the described changes were no longer observed.

Animals↗
PubMed1983

Effects of giving ethionine on the parathion-metabolizing enzymes in the liver of fasted calves.

DL-Ethionine (0.87 g/kg) or saline solution (equivalent volume) was administered IV to 4-month-old calves which had been fasted 60 hours before slaughter. The livers of the ethionine-treated calves were large, had a high lipid content, and were diffusely pale yellow on the cut surface. The livers of the saline-treated group were shrunken. In liver samples from calves of both groups, there was reduced parathion and paraoxon metabolism. In the ethionine-treated group, parathion desulfuration also was reduced. In all cases, the changes were greater in the ethionine-treated animals. Fasting of calves with saline solution or ethionine treatment caused a lowering of the liver biotransformation of parathion and paraoxon.

Animals↗
PubMed1977

Studies on drug metabolism and liver ultrastructure after conjoint treatment with pregnenolone-16alpha-carbonitrile and dl-ethionine.

Zoxazolamine paralysis, hexobarbital anesthesia and digitoxin convulsions were diminished in rats by 3 days of pretreatment with pregnenolone-16alpha-carbonitrile (PCN). Simultaneous injection of dl-ethionine did not block this effect of PCN. Dl-Ethionine decreased, while PCN or PCN + ethionene increased, zoxazolamine metabolism by the 9,000g supernatant fraction of the liver. Dl-ethionine neutralized the influence of PCN and phenobarbital on zoxazolamine metabolism in rats that were pretreated with PCN or phenobarbital for 1 day, and it inhibited the action of phenobarbital on hexobarbital anesthesia. PCN augmented the liver weight of animals given dl-ehtionine whereas dl-ethionine in itself did not. PCN produced SER proliferation in hepatocytes and dl-ethionine caused lipid accumulation, SER proliferation and myelin-figure formation. When administered conjointly, these compounds had an additive effect on the liver cell ultrastructure.

Animals↗
PubMed1976

Mechanism of suppressive effect of basic cupric acetate on rat liver carcinogenesis by ethionine.

The rate of ethylation of t-RNA in vivo by L-ethionine[ethyl-1-14C] markedly lowered in the liver of rats fed a diet containing copper than that of control. In corporation of the labeled compound into the t-RNA of liver by a single injection. of L-ethionine[ethyl-1-14C] was inhibited as much as 50% by the preceding concurrent administration of copper and ethionine added in the diet to rats. Direct interaction of copper ion with ethylation by ethione in the specific t-RNA of the rat liver was examined as an important biochemical explanation in molecular level for the inhibitory mechanism of copper on rat liver carcinogenesis by ethionine. Profiles of normal t-RNA on methylated albumin-kieselguhr column chromatography revealed three components for leucine, two of which were found at the tube number 40 to 50 and disappeared in the leucyl t-RNA treated with ethionine. The components for leucine that disappeared were normalized in the liver of rats by the concurrent administration of copper.

Adenosine↗
PubMed1986

Ethionine in the analysis of the possible separate roles of methionine and choline deficiencies in carcinogenesis.

The importance of ethionine, the ethyl analogue of methionine, as a metabolic probe to study the possible roles of methionine and choline in liver carcinogenesis has been briefly reviewed. Ethionine-induced liver carcinogenesis is similar in many aspects, including initiation, promotion, and progression, to carcinogenesis with other agents. However, the special role of methionine in preventing virtually all metabolic and pathologic effects of ethionine, including liver cancer, places ethionine in a special position. On the basis of these observations and our current knowledge about choline deficiency in the genesis of liver cancer, we proposed that choline and methionine play separate but overlapping roles in the initiation and promotion of liver carcinogenesis.

Animals↗
PubMed1982

Alpha-fetoprotein dynamics during ethionine-induced hepatocarcinogenesis in rat.

Rats fed on a diet containing 0.25% DL-ethionine (ethionine), which has been usually used as carcinogenic dose, demonstrated the early elevations of serum alpha-fetoprotein (AFP) approximately in week 6 of the feedings. After declining once between week 10 and 14, the serum AFP levels increased again in week 22 of the continuous feeding, when well differentiated hepatocellular carcinoma had already developed. The level of serum AFP after development of hepatoma was found to be lower than those seen during the early elevation of AFP. Furthermore, in ethionine-induced hepatoma-bearing rats, AFP levels in the tumors were rather low as compared to those in the nontumorous portions of the liver surrounding the tumors. The results indicated that ethionine-induced hepatocellular carcinoma is not an AFP-highly-producing tumor.

Animals↗
PubMed1982

Influence of methionine administration on serum alpha-fetoprotein levels in ethionine-injured rats.

Serum alpha-fetoprotein (AFP) concentrations increased promptly 2 days following a single injection of DL-ethionine (ethionine) in adult female rats. Continuous elevation of serum AFP was also observed on feeding a diet containing 1% ethionine for at least 2-3 weeks. A rise of serum AFP was not found if the diet was supplemented with 2.8% methionine. Furthermore, in rats fed on 1% ethionine for 2 weeks, dietary change to the laboratory chow supplemented with and without 2.8% methionine produced a decrease of increased serum AFP levels.

Animals↗
PubMed1984

Cyclic AMP binding activity in liver supernatants during acute ethionine intoxication.

There is a significant increase in hepatic cAMP binding activity 4 hr following ethionine intoxication. This activity is localized to the 100, 000 g supernatant. The binding of cAMP by the 100, 000 g supernatant of controls can be increased to experimental levels simply by dialysis. The increased binding activity seen during ethionine intoxication can be reversed by the administration of adenine. Neither S-adenosyl ethionine, S-adenosyl methionine, S-adenosyl homocysteine, nor AMP compete effectively with cAMP for the binding protein. Increasing ADP concentrations stimulates cAMP binding whereas increasing ATP concentration inhibits cAMP binding. At concentrations seen during ethionine intoxication the effects of ADP and ATP were equal but opposite in direction.

Adenine↗