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PubMed1982

Hepatic levels of S-adenosylethionine and S-adenosylmethionine in rats and hamsters during subchronic feeding of DL-ethionine.

The levels of S-adenosylethionine (AdoEt) and of S-adenosylmethionine (AdoMet) in the livers of weanling male rats and male and female hamsters fed ethionine for 1-6 weeks were determined. Ethionine was fed at levels of 0, 0.1, and 0.3% in the diet, and the animals were sacrificed after 0, 1, 3 and 6 weeks of treatment. In both species the hepatic contents of AdoEt were dependent upon the level of ethionine in the diet. For the 6-week experimental period the hepatic levels of AdoEt average 81 microgram/g liver in male hamsters fed 0.1% ethionine in the diet and 160 microgram/g in those fed 0.3% ethionine; the corresponding AdoEt levels in female hamsters were 104 and 191 microgram/g liver, respectively. No marked shifts in hepatic AdoEt levels were seen in either male or female hamsters although a gradual rise in hepatic AdoEt from 145 to 233 microgram/g was noted in the female hamsters receiving 0.3% ethionine in the diet for 1-6 weeks. AdoEt levels in the livers of rats fed 0.3% ethionine were quite variable with values of 123, 305 and 127 microgram/g liver noted at weeks 1, 3 and 6 respectively. In rats fed the 0.1% ethionine diet the liver AdoEt levels dropped from 103 to 61 microgram/g from weeks 1 to 6, In animals fed the ethionine-free diet, the hepatic contents of AdoMet were relatively constant throughout the 6-week experimental period, with average values of 25, 17, and 29 microgram/g liver respectively in the male rats, male hamsters and female hamsters. Chronic ethionine administration always suppressed hepatic AdoMet levels. This suppression was generally greater in animals fed the 0.1% ethionine than in those fed the 0.3% ethionine diet. Thus, the average hepatic AdoMet level in rats, male hamsters and female hamsters receiving the 0.1% ethionine diet for 3-6 weeks were 32, 18, and 45% respectively, of the corresponding AdoMet levels in control animals: however, the corresponding AdoMet levels in animals receiving the 0.3% ethionine diet were 66, 42, and 62% of the respective control values. Feeding 0.1% ethionine to male hamsters led to exceedingly low levels of liver AdoMet (1.4-2.9 microgram/g). No direct correlations could be made between the effects of ethionine feeding on the hepatic AdoEt and AdoMet levels in rats and hamsters and the previously reported differences in carcinogenicity by ethionine in these species.

Adenosine↗
PubMed1975

The effect of cupric acetate on ethionine metabolism.

The addition of cupric acetate, a potent inhibitor of ethionine carcinogenesis, to a diet containing ethionine increased the ethionine toxicity. The concentration of S-adenosylethionine in liver was found to be significantly higher when compared to animals fed only ethionine in the diet. Ethionine forms a complex(es) with cupric acetate that is insoluble at a pH higher than 4; however, this complex can be solubilized at a low pH. Ethionine, if administered p.o. in the form of this complex, was absorbed from the intestinal lumen in the same order of magnitude as when administered alone; however, as the body weight increased over 200 g, the portion of absorbed ethionine decreased. The absorption of ethionine bound in the complex was completed within 16 hr compared to 2 hr for free ethionine. This time delay was accompanied by a shift in the concentration maximum of ethionine metabolities in the liver form 8 to 24 hr. When ethionine was administered alone, it was metabolized in the intestinal lumen as demonstrated by the analysis of the soluble intestinal contents; the presence of cupric acetate inhibited this process. The chromatographic analysis of ethionine metabolites in urine of rats treated by the complex revealed an increased excretion of ethionine sulfoxide and other ethionine metabolities at the expense of N-acetylethionine sulfoxide. The increased concentration of S-adenosylethionine in the liver in chronic experiments may be, at least partly, a result of a diminished capacity of the rat to detoxify (acetylate) ethionine sulfoxide, which is considered the main reserve pool of ethionine for the maintenance of a high level of S-adenosylethionine.

Animals↗
PubMed1997

Suppression by phenobarbital of ethionine-induced hepatocellular carcinoma formation and hepatic S-adenosylethionine levels.

An 18-month carcinogenicity study was conducted in male weanling F344 rats (28/group) to examine the effects of the simultaneous feeding of selected concentrations of ethionine and 0.05% phenobarbital in a normal chow diet. The effects of a 1-6-week feeding of phenobarbital and ethionine on the hepatic levels of the related metabolites S-adenosylmethionine, S-adenosylhomocysteine and S-adenosylethionine were also examined. Ethionine at 0.3% or 0.1% induced hepatocellular carcinoma (HCCa) at incidences of 90% (19/21) and 89% (24/27), respectively. Adding phenobarbital to the 0.1% ethionine diet reduced the incidence of HCCa to 36% (10/28) and reduced the number of liver tumor-associated deaths occurring prior to terminal sacrifice from 10/27 to 1/28. No hepatic tumors were observed in rats fed 0, 0.003, 0.01, or 0.03% ethionine. Phenobarbital alone or combined with 0.03% ethionine produced no hepatic tumors. Dietary ethionine at 0.1% reduced the intracellular hepatic level of S-adenosylmethionine to <50% of that seen in control rats. Phenobarbital alone had little effect on either S-adenosylmethionine or S-adenosylhomocysteine levels. The combination of phenobarbital and 0.1% ethionine led to increases in the hepatic levels of S-adenosylmethionine of 40-60% after 3 and 6 weeks of feeding, compared to those seen in rats receiving 0.1% ethionine alone. Ethionine feeding resulted in high levels of S-adenosylethionine in the livers. Combining phenobarbital with ethionine in the diet led to 30-50% reductions in hepatic S-adenosylethionine content. The results indicate that phenobarbital inhibits hepatocarcinogenesis by ethionine, that ethionine may cause HCCa via methyl group insufficiency, and that at levels of < or =0.03% ethionine did not show evidence of tumorigenicity.

Adenosine↗
PubMed1977

Hyperglucagonemia and altered responsiveness of hepatic adenylate cyclase-adenosine 3',5'-monophosphate system to hormonal stimulation during chronic ingestion of DL-ethionine.

Basal activity and hormonal responsiveness of the adenylate cyclase-adenosine 3',5'-monophosphate system were examined in premalignant liver from rats chronically fed the hepatic carcinogen DL-ethionine, and these data were correlated with endogenous levels of plasma glucagon. By 2 weeks basal hepatic cyclic AMP levels, determined in tissues quick-frozen in situ, were 2-fold higher in rats ingesting ethionine than in the pair-fed control. Enhanced tissue cyclic AM content was associated with an increase in the adenylate cyclase activity of whole homogenates of fresh liver from rats fed ethionine (68 +/- 5 pmol cyclic AMP/10 min per mg protein) compared to control (48 +/- 4). Cyclic AMP-dependent protein kinase activity ratios were also significantly higher (control, 0.38 +/- 0.04; ethionine 0.55 +/- 0.05) and the percent glycogen synthetase activity in the glucose 6-phosphate-independent form was markedly reduced (control, 52 +/- 7%; ethionine, 15 +/- 1.5%) in the livers of ethionine-fed rats compared to the controls, suggesting that the high total hepatic cyclic AMP which accompanied ethionine ingestion was bilogically effective. These changes persisted throughout the 38 weeks of drug ingestion. Immunoreactive glucagon levels, determined in portal venous plasma, were 8-fold higher than control after 2 weeks of the ethionine diet (control, 185 +/- 24 pg/ml; ethionine, 1532 +/- 195). Analogous to the changes in hepatic parameters, plasma glucagon levels remained elevated during the entire period of drug ingestion until the development of hepatomas. The hepatic cyclic AMP response to a maximal stimulatory dose of injected glucagon was blunted in vivo in ethionine-fed rats (control, 14 -fold increase over basal, to 8.63 +/- 1.1 pmol/mg wet weight; ethionine, 4.6-fold rise over basal, to 5.42 +/- 0.9). Reduced cyclic AMP responses to both maximal and submaximal glucagon stimulation were also evident in vitro in hepatic slices prepared from rats fed the drug, and the reduction was specific to glucagon. Absolute or relative hepatic cyclic AMP responses to maximally effective concentrations of protaglandin E1 or isoproterenol in hepatic slices from ethionine-fed rats were greater than or equal to those observed in control slices. Parallel alterations in hormonal responsiveness were observed in adenylate cyclase activity of whole homogenates of these livers, implying that the changes in cyclic AMP accumulation following hormone stimulation were related to an alteration in cyclic AMP generation in the premalignant tissue. In view of the recognized hepatic actions of glucagon and the desensitization of adenylate cyclase which can occur during sustained stimulation of the liver with this hormone, the endogenous hyperglucagonemia that accompanies ethionine ingestion could play a role in the pathogenesis of both the basal alterations in hepatic cyclic AMP metabolism and the reduced responsiveness to glucagon observed in liver from rats fed this carcinogen.

Adenylyl Cyclases↗
PubMed1975

The metabolism of ethionine in rats.

The L-[ethyl-1-14C]ethionine metabolites soluble in trichloroacetic acid were studied in rats by the use of column chromatography. After p.o. application of ethionine, its absorption from intestinal lumen was rapid and was complete in less than 2 hr. Any unabsorbed ethionine was later excreted in the feces. During the passage through the gastrointestinal tract, a portion of ethionine was metabolized. The chemical nature and biological significance of these metabolites is not yet known. The fate of absorbed ethionine was investigated in the small intestine, liver, blood, kidney, and urine as a function of time after application. A great part of ethionine was quickly oxidized to ethionine sulfoxide. In liver and kidney, the concentration of ethionine sulfoxide was higher than that of free ethionine. In all organs, the presence of N-acetylethionine sulfoxide was also demonstrated. Ethionine sulfoxide can be reduced and N-acetylethionine can be deacetylated in vivo as demonstrated by the formation of S-adenosylethionine from ethionine sulfoxide and N-acetylethionine. In urine, 4 main components were observed: N-acetylethionine sulfoxide, S-adenosylethionine, ethionine sulfoxide, and free ethionine. Some minor components, as yet unidentified, were also present in the urine and in different organs. The probable site of origin of urinary S-adenosylethionine is the kidney.

Acetylation↗
PubMed1987

Function of reticuloendothelial system on ethionine induced liver injury in mice.

Phagocytic activity as a function of the reticuloendothelial system (RES) has been studied in ethionine induced liver injury by using the carbon clearance test. Liver damage in male and female mice was induced by DL- and L-ethionine injections (1000 mg/kg/day, i.p.). In both female and male mice, a single dose or three injections of DL- or L-ethionine caused increases in liver/body weight ratio, A/G ratio, GOT and GPT levels, and BSP retention. There was the decrease of the total protein levels in the serum. The degree of liver injury was more severe after three injections of DL- and L-ethionine than after a single injection of them. After a single injection of ethionine, the L-isomer induced a slightly greater response than the racemic mixture, except for BSP retention. On the other hand, phagocytic activities by the carbon clearance test were increased after a single injection or three injections of DL- and L-ethionine. That is, the K value was increased in all ethionine treated mice except for females with three injections of DL-ethionine. The alpha value was increased after three injections in DL- and L-ethionine treated males and DL-ethionine treated females. In addition, the increase in carbon uptake by Kupffer cells can be seen by light microscopy after a single injection or three injections of DL- or L-ethionine. These findings indicate that ethionine injections induce the enhancement of RES phagocytosis, although the biochemical parameters indicating liver injury are changed severely. These results support the data indicating no correlation between the alteration of RES activity and the degree of liver injury.

Alanine Transaminase↗
PubMedDate not supplied

Evaluation of d,l-ethionine as a mechanism for pancreatic islet regeneration in dogs.

OBJECTIVE: To determine whether induction of pancreatic necrosis and islet proliferation by d,l-ethionine has potential for treating dogs with beta-cell insufficiency. DESIGN: Eighteen mixed breed dogs of both sexes were given d,l-ethionine at 100 mg/kg three times weekly for 2 weeks; 6 dogs were euthanased at 2, 14 and 28 d after the last dose. METHODS: Clinical signs during administration and recovery were assessed. Routine biochemical analyses were performed before each ethionine dose and then once weekly. Faecal samples were examined weekly for malassimilated nutrients and blood. Blood coagulation screening tests (OSPT and APTT) were determined on four dogs after ethionine administration. Intravenous glucose tolerance tests were conducted before the first and after the last ethionine dose and then fortnightly. All dogs were necropsied and pancreas, liver, kidney and jejunum were examined microscopically. RESULTS: During ethionine administration all animals displayed vomiting, inappetence, diarrhoea (often with blood), weight loss and depression. Three dogs were euthanased prematurely due to severe illness, but those allowed to recover were eating and brighter 7 d after cessation of ethionine administration. Serum concentrations of TLI, amylase and lipase increased initially, then decreased, during administration but retumed to normal during recovery. Concentrations of ALT, ALP, unconjugated and conjugated bilirubin increased during administration then decreased slowly. Histological examination revealed hepatic lipidosis and necrosis, but no renal or jejunal lesions. In most dogs, faecal examination demonstrated increased undigested starch and muscle, as well as increased digested and undigested fat, during ethionine administration or early during the recovery period, suggesting transient malassimilation. APTT was unchanged but OSPT was prolonged in all dogs. There was no impairment of insulin secretion or glucose intolerance and C-peptide concentrations were unaffected. Immediately after ethionine administration there was delayed insulin degradation and by day 43 there was evidence of increased insulin sensitivity. CONCLUSION: d,l-ethionine administration in dogs appeared not to interfere with insulin secretion, but caused clinical signs and laboratory changes indicative of pancreatic exocrine necrosis, severe hepatobiliary disease and transient malassimilation. Pancreatic and hepatic dysfunction was severe but clinical recovery occurred after ethionine administration ceased. The severe side-effects observed with d,l-ethionine should preclude its potential use for treating diabetes mellitus in dogs.

Alanine Transaminase↗
PubMed1982

Inhibitory effects of ethionine, an analogue of methionine, on wool growth.

Varying amounts of DL-, L- or D-ethionine were administered intravenously to sheep, either as a continuous infusion, usually over 2 days, or as a single injection. Groups of sucking mice and rats, in their first cycle of hair growth, were given subcutaneous injections of DL-ethionine at several dose rates. Ethionine was a potent inhibitor of wool growth in sheep; the L- and D-isomers appeared equally effective. An infusion of 20 mg/kg DL-ethionine (c. 50 mg/kg0.75) given at a daily rate of 10 mg/kg for 2 days, or an injection of 40 mg/kg DL-ethionine (c. 100 mg/kg0.75), were sufficient to cause the growth of very weak wool and allow the fleece to be readily removed by hand within 3 weeks after dosing. The inhibition of wool growth was usually associated with a concentration of ethionine in blood plasma, during intravenous infusion, of 10 mumol/l or higher. An infusion of DL-ethionine at a daily rate of 1 mg/kg for 12 days caused the growth of weak fibres and substantially reduced both length growth rate and diameter of fibres. The toxicity of ethionine to sheep was dependent on the total dose and the duration of administration. An infusion of 40 mg/kg (20 mg/kg daily for 2 days) produced severe effects, but the sheep recovered; a dose of 14 mg/kg (2 mg/kg daily for 7 days) was lethal. The effects of ethionine on wool growth were reduced or prevented by the concurrent infusion of methionine (10-15 mol/mol ethionine). Doses of DL-ethionine as high as 460 mg/kg0.75 failed to cause hair loss in sucking mice. While body growth was severely retarded at this dose, no deaths occurred. Likewise, DL-ethionine failed to cause hair loss in sucking rats, but was lethal to some rats at a dose of 360 mg/kg0.75.

Animals↗
PubMed1988

Genetic analysis of L-ethionine-mediated induction of alpha-fetoprotein in mice.

Two genetic loci regulate hepatic alpha-fetoprotein (AFP) mRNA levels in adult mice. The raf locus controls basal levels and the Rif locus determines the degree of induction during liver regeneration. We have investigated the function of each locus during L-ethionine-mediated AFP induction using adult female mice with different Rif/raf genotypes. A single intraperitoneal injection of L-ethionine (0.5 mg/g body weight) resulted in significant triglyceride accumulation in hepatic parenchymal cells and increased AFP synthesis 48-96 h following injection. Hepatic AFP mRNA levels in Balb/cJ mice (high basal level/high induction level during regeneration) were 10- to 30-fold higher than Balb/cCRBL or C3H/He mice (low basal level/high induction level) following ethionine injection, indicating that raf-mediated differences persisted throughout the course of acute ethionine poisoning. The magnitude of this induction was similar to that seen during carbon tetrachloride-induced regeneration. In contrast, C57BL/6 mice (low basal level/low induction level during regeneration) contained hepatic AFP mRNA levels similar to Balb/cCRBL and C3H/He mice following ethionine injection. Thus, Rif-dependent differences seen during liver regeneration were not seen during acute ethionine poisoning. This leads us to conclude that (1) hepatic AFP mRNA induction by ethionine may not be mediated by the Rif locus if Rif is a transcriptional inducer, or (2) if Rif is a transcriptional repressor, it is inactivated equally in all strains during acute ethionine poisoning, unlike during liver regeneration. Hepatic albumin mRNA levels were not affected by ethionine treatment in vivo. L-Ethionine elevated AFP mRNA levels in primary mouse hepatocyte cultures; however, ethionine treatment also increased albumin mRNA levels in vitro.

Albumins↗
PubMed1998

Ethionine toxicity in vitro: the correlation of data from rat hepatocyte suspensions and monolayers with in vivo observations.

The hepato-steatogenic compound ethionine has been used to investigate the correlations between in vivo and in vitro toxicity data. The aim was to find a suitable model of toxicity in hepatocyte suspensions or monolayers in vitro, which could predict the known toxicity of ethionine in vivo and which could be implemented in screening compounds of unknown toxicity. Thus a variety of markers of cytotoxicity, metabolic competence and liver-specific functions were investigated in rat hepatocyte suspensions and monolayers and compared with in vivo data in the rat. The following markers were measured in the appropriate system: (1) Neutral red uptake; 3-(4,5 dimethyl)thiazol-2-yl,-2,5-diphenyl tetrazolium bromide (MTT) reduction; lactate dehydrogenase (LDH), aspartate aminotransferase (AST) and alanine aminotransferase (ALT) leakage (cytotoxicity). (2) ATP levels, protein synthesis and glutathione (GSH) levels (metabolic competence). (3) Urea and triglyceride synthesis and beta-oxidation (liver specific functions). Ethionine (0-30 mM) did not affect the markers of direct cytotoxicity, except neutral red uptake, which was reduced by 18 and 30 mM ethionine after 20 h in culture. ATP and GSH depletion occurred in hepatocyte suspensions at the highest concentrations of ethionine (20 and 30 mM) after 1 h. In monolayers, GSH levels were reduced after 4 h, but not 20 h. Urea synthesis was increased in hepatocyte suspensions from 1 to 3 h by 10-30 mM ethionine and reduced after 20 h in cultured hepatocytes (18-30 mM). Protein synthesis was reduced and beta-oxidation was increased in ethionine-treated hepatocyte suspensions. Unfortunately, there was no measurable effect on triglyceride accumulation within cells (the major biochemical change in vivo) in either system. Ethionine treated hepatocytes in suspension showed the same rate of triglyceride synthesis and transportation out of cells as control cells. Thus, hepatocyte suspensions were able to mimic the early biochemical effects of ethionine in vivo (ATP and GSH depletion, inhibition of protein synthesis) and some effects on urea synthesis, but monolayer cultures appeared to be less sensitive to the toxicity of ethionine. However, neither in vitro system was able to model the effects of ethionine on the accumulation of triglycerides in vivo.

Adenosine Triphosphate↗
PubMed1989

Changes in peroxisomes and mitochondria in liver of ethionine exposed rats: a biochemical and morphological investigation.

Administration of ethionine resulted in a dose- and time-dependent enhancement of the activities of peroxisomal beta-oxidation, carnitine palmitoyltransferase and omega-oxidation, especially the 12-hydroxylation of lauric acid. The mitochondrial and, especially, the microsomal palmitoyl-CoA hydrolase activities were increased, whereas the peroxisomal and cytosolic activities were decreased. Ethionine administration decreased the catalase and urate oxidase activities in both a dose- and time-related manner. The liver cells and the volume fraction of cytoplasma decreased 40% in ethionine-exposed animals, whereas the average nuclei volume fraction increased approximately 50%. The volume fraction and the total number of mitochondria increased 1.5-fold after ethionine exposure and an accumulation of lipid in large droplets of the hepatocytes was observed. No proliferation of peroxisomes was observed after treatment; the volume fraction and the number of peroxisomes decreased. However, the size of peroxisomes in livers of ethionine-exposed rats tended to be greater than controls; a 1.5-fold increase in average size was observed. As there was no induction of the protein content of the bifunctional enoyl-CoA hydratase, an enzyme involved in peroxisomal beta-oxidation, it is considered that ethionine selectively stimulates the peroxisomal beta-oxidation due to increased peroxisome surface area rather than evoked a peroxisome proliferation capacity. Increased peroxisomal beta-oxidation was also observed in the kidney of ethionine-exposed rats at a dose of 750 mg/day/kg body weight. At that dose the amount of reduced glutathione (GSH) was significantly increased in kidney. The amount of GSH and the level of peroxisomal beta-oxidation were significantly increased in liver at an ethionine dose of 100 mg/day/kg body weight. These responses in liver were evident within 2 days of ethionine exposure and then leveled off whereas a significant increase in GSH and peroxisomal beta-oxidation in kidney was observed within 12 days. Whether the acute H2O2-generating peroxisomal oxidation of long-chain fatty acids in the liver may also make this organ susceptible to the long-term effects of low-dose ethionine and be an important step in the chain of events which eventually results in tumour development should be considered.

Acid Phosphatase↗