Liver Ethionine

One type of fatty liver that has been smdied extensively in rats is due to a deficiency of choline, which has therefore been called a lipotropic factor. The antibiotic puromycin, ethionine (a-amino-y-mercaptobu-tyric acid), carbon tetrachloride, chloroform, phosphorus, lead, and arsenic all cause fatty liver and a marked reduction in concentration of VLDL in rats. Choline will not protect the organism against these agents but appears to aid in recovery. The action of carbon tetrachloride probably involves formation of free radicals... 

Reynolds ES. 1972. Comparison of early injury to liver endoplasmic reticulum by halomethanes, hexachloroethane, benzene, toluene, bromobenzene, ethionine, thioacetamide and dimethylnitrosamine. 

This is the accumulation of triglycerides in hepatocytes, and there are a number of mechanisms underlying this response as is discussed below (see the sect. "Mechanisms of Toxicity"). The liver has an important role in lipid metabolism, and triglyceride synthesis occurs particularly in zone 3. Consequently, fatty liver is a common response to toxicity, often the result of interference with protein synthesis, and may be the only response as after exposure to hydrazine, ethionine, and tetracycline, or it may occur in combination with necrosis as with carbon tetrachloride. It is normally a reversible response, which does not usually lead to cell death, although it can be very serious as is the case with tetracycline-induced fatty liver in humans. Repeated exposure to compounds, which cause fatty liver, such as alcohol, may lead to cirrhosis. 

This is a chronic lesion resulting from repeated injury and subsequent repair. It may result from either hepatocyte damage or cholestatic damage, each giving rise to a different kind of cirrhosis. Thus, carbon tetrachloride will cause liver cirrhosis after repeated exposure, but also compounds, which do not cause acute necrosis, such as ethionine and alcohol may cause cirrhosis after chronic exposure. 

After a single dose of ethionine, triglycerides accumulate in the liver, the increase being detectable after four hours. After 24 hours, the accumulation of triglycerides is maximal, being 15 to 20 times the normal level. Initially, the fat droplets accumulate on the endoplasmic reticulum in periportal hepatocytes and then in more central areas of the liver. Some species develop hepatic necrosis as well as fatty liver, and nuclear changes and disruption of the endoplasmic reticulum may also be observed. 

The exact mechanism underlying the carcinogenesis is less clear, but presumably involves inhibition of RNA synthesis or the production of abnormal ethylated nucleic acids and hence disruption of transcription, translation, or possibly replication. It is of interest that ethionine is not mutagenic in the Ames test, with or without rat liver homogenate. However, ethionine may be carcinogenic after metabolism to vinyl homocysteine (in which vinyl replaces ethyl), which is highly mutagenic. 

Ethionine is a hepatotoxic analogue of methionine causing fatty liver (accumulation of triglycerides). Chronic exposure causes cirrhosis, bile duct proliferation, and heptatocellular carcinoma. It forms S-adenosyl ethionine, which traps adenosyl leading to ATP depletion, which reduces triglyceride export from the liver. It also leads to ethylated bases in DNA. 

Galactosamine and ethionine both cause liver dysfunction. Comment on the similarities and differences between these two hepa to toxicants. 

Chemicals which can damage (a) the liver include carbon tetrachloride, paracetamol, bromobenzene, isoniazid, vinyl chloride, ethionine, galactosamine, halothane, dimethyl-nitrosamine (b) the kidney include hexachlorobutadiene, cadmium and mercuric salts, chloroform, ethylene glycol, aminoglycosides, phenacetin (c) the lung include paraquat, ipomeanol, asbestos, monocrotaline, sulfur dioxide, ozone, naphthalene (d) the nervous system include MPTP, hexane, organophosphoms compounds, 6-hydroxydopamine, isoniazid (e) the testes include cadmium, cyclophosphamide, phthalates, ethanemethane sulfonate, 1,3-dinitrobenzene (f) the heart include allylamine, adriamycin, cobalt, hydralazine, carbon disulfide (g) the blood include nitrobenzene, aniline, phenyl-hydrazine, dapsone. 

Phenanthroline, on the other hand, stimulates the activity of some enzymes, perhaps by removing a metal that is inhibitory to the enzyme.523 524 It can induce porphyrin synthesis525 and improve the rate of ascorbate oxidation.526 It induces lysis of sensitized sheep erythrocytes.527 It is reported to reverse the resistance of microorganisms to penicillins.528 It binds to an immunoglobulin.529 It also protects rat liver from injury induced by dimethylnitrosamine530 and ethionine.531... 

Barone C, Cittadini A, Galeotti T, et al. 1973. The effect of intoxication induced in rat liver by carbon tetrachloride, ethionine, and white phosphorus on the level of microsomal cytochromes b5 and P450. Experientia 29 73-74. 

In complementary experiments Billing and Weinbren (cited in BIO) infused bilirubin in amounts sufficient to saturate the capacity of the liver to excrete the pigment and noted that, in addition to bilirubin, pigment I but no pigment II accumulated in the plasma. The liver poisons ethionine and icterogenin also cause an accumulation of pigment I but not of pigment II in the blood of experimental animals (B13). 

It is of some interest to inquire whether one may affect the net synthesis of fibrinogen under conditions of extreme hypofibrinogenemia associated with maximal fibrinogen production. Table I reveals that the amino acid analog L-ethionine, 5.6 mg. at the outset of liver perfusion, followed by continuous infusion of 3 mg. per hour after an initial priming dose, greatly suppresses the biosynthesis of fibrinogen. 

The view that this is true net biosynthesis of fibrinogen is supported by a variety of ancillary observations. Fibrinogen biosynthesis is suppressed in the presence of metabolic analogs, such as L-ethionine and puromycin, most markedly by the latter in spite of the maximal stimulus for production. Mitomycin C, which is believed to interfere with biosynthetic processes in the nucleus, also caused some suppression of fibrinogen biosynthesis. The isolated perfused liver in the presence of any of the three inhibitors used continues to function in an apparently normal manner in terms of bile secretion, linear urea production, amino acid oxidation, and glucose utilization. The effects of these inhibitors on the biosynthesis of the other plasma proteins will be described elsewhere. 

Ethionine is an acutely toxic compound that targets the liver and pancreas in animals, and possibly humans. Ethionine inhibits intracellular S-adenosy-Imethionine mediated methylation, and cause widespread liver and pancreatic necrosis. 

Ethionine was detected in the liver, plasma, kidney, small intestine, and red blood cells (in the order of decreasing concentration) of rats after 8h oral... 

Ethionine-induced teratogenesis has been reported in rats and chicks. Both mice and rats demonstrate significant strain difference to the carcinogenic effects that are caused by ethionine. In addition to cancer, the ethionine-induced abnormal methylation may also have pathological effects leading to birth defects, neurological disorder, and liver and pancreatic toxicities. 

Tumors were formed in the lung, thorax, respiratory tract, and liver in mice study after 2 year oral administration with high dosages. Low chronic doses of ethionine exposure result in irreversible testicular lesions in rats. 

Ethionine-induced hepatocellular carcinoma was reduced from 89% to 36% by adding phenobarbital to the 0.1% ethionine diet in F344 rats during an 18-month carcinogenicity study. A different study showed vitamin E protects rat liver mitochondria from ethionine toxicity. 

Platt DS, Cockrill BL. 1969. Biochemical changes in rat liver in response to treatment with drugs and other agents. II. Effects of halothane, DDT, other chlorinated hydrocarbons, dimethyinitrosamine and ethionine. Biochem Pharmacol 18 445-457. 

In some experiments concerned with the mechanism by which tryptophan acted to improve hepatic protein synthesis after toxic injury, the ability of tryptophan to stimulate hepatic mRNA synthesis, nucleocytoplasmic translocation of RNA in vitro, and nuclear envelope nucleoside triphosphatase activity after hepatotoxic injury was measured.188 Nucleoside triphosphatase (Mg2+-dependent adenosine triphosphatase, EC 3.6.1.3.1) was assayed since it is present in mammalian liver nuclear envelopes,224 and there is evidence that this enzyme is involved in nucleocytoplasmic translocation of RNA.221 All of these parameters were elevated significantly by tryptophan after agents such as actinomycin D, cordycepin, ethionine, puromycin, and hypertonic NaCl demonstrated a curative effect by tryptophan, but not after tryptophan following CC14, NaF, and sparsomycin demonstrated no improvement with tryptophan. These findings emphasized the importance of the role that tryptophan plays in stimulating the availability of cytoplasmic... 

Sarma, D. S., Reid, I. M., Verney, E., and Sidransky, H., Studies on the nature of attachment of ribosomes to membranes in liver. I. Influence of ethionine, sparsomycin, CC14, and puromycin on membrane-bound polyribosomal disaggregation and on detachment of membrane-bound ribosomes from membranes, Lab. Invest., T7, 39, 1972. 

Ethionine is a hepatotoxic analogue of the amino acid methionine (figure 7,4 E). Ethionine is an antimetabolite which has similar chemical and physical properties to the naturally occurring amino acid. After acute doses ethionine causes fatty liver but prolonged administration results in liver cirrhosis and hepatic carcinoma. Some of the toxic effects may be reversed by the administration of methionine. The effects may be produced in a variety of species, athough there are differences in response. The rat also shows a sex difference in susceptibility, the female animal showing the toxic response rather than the... 

After a single dose of ethionine, triglycerides accumulate in the liver, the increase being detectable after four hours. After 24 hours the accumulation of triglycerides is maximal, being 15-20 times the normal... 

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