Ethionine

Similarly, by adding analogs of L-methionine, the methylation of C6 is inhibited, resulting in the formation of 6-demethylchlortetracycline. The analogs that may be used include D-methionine and ethionine. 

Biocatalytic access to both antipodal sulfoxides was exploited in total syntheses of bioactive compounds, which is outlined in some representative examples. Biooxidation of functionalized dialkyl sulfides was utilized in the direct synthesis of both enantiomers of sulforaphane and some analogs in low to good yields and stereoselectivities (Scheme 9.27) [206]. This natural product originates from broccoli and represents a potent inducer of detoxification enzymes in mammalian metabolism it might be related to anticarcinogenic properties of plants from the cruciform family. All four possible stereoisomers of methionine (R = Me) and ethionine sulfoxides... 

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. 

Depletion of ATP is caused by many toxic compounds, and this will result in a variety of biochemical changes. Although there are many ways for toxic compounds to cause a depletion of ATP in the cell, interference with mitochondrial oxidative phosphorylation is perhaps the most common. Thus, compounds, such as 2,4-dinitrophenol, which uncouple the production of ATP from the electron transport chain, will cause such an effect, but will also cause inhibition of electron transport or depletion of NADH. Excessive use of ATP or sequestration are other mechanisms, the latter being more fully described in relation to ethionine toxicity in chapter 7. Also, DNA damage, which causes the activation of poly(ADP-ribose) polymerase (PARP), may lead to ATP depletion (see below). A lack of ATP in the cell means that active transport into, out of, and within the cell is compromised or halted, with the result that the concentration of ions such as Na+, K+, and Ca2+ in particular compartments will change. Also, various synthetic biochemical processes such as protein synthesis, gluconeogenesis, and lipid synthesis will tend to be decreased. At the tissue level, this may mean that hepatocytes do not produce bile efficiently and proximal tubules do not actively reabsorb essential amino acids and glucose. 

Figure 7.64 The role of methionine in methylation reactions and the mechanisms underlying ethionine hepatotoxic-r. ity. After the substrate is methylated, the S-adenosyl homocysteine remaining is broken down into homocysteine and adenine, both of which are reused. When S-adenosyl ethionine is formed, however, this recycling is reduced (=), and a shortage of adenine and hence ATP develops.

Ethionine is a hepatotoxic analogue of the amino acid methionine (Fig. 7.64). Ethionine is an antimetabolite, which has similar chemical and physical properties to the naturally occurring... 

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. 

S-Adenosyl ethionine carries out ethylation reactions or ethyl transfer, and this is presumably involved in the carcinogenesis. Administration of ethionine to animals leads to the production of ethylated bases such as ethyl guanine. This may account for the observed inhibition of RNA polymerase and consequently of RNA synthesis. Incorporation of abnormal bases into nucleic acids and the production of impaired RNA may also lead to the inhibition of protein synthesis and misreading of the genetic code. 

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. 

Similarities Both galactosamine and ethionine are toxic as a result of interference with intermediary metabolism. Galactosamine depletes UTP, ethionine depletes ATP. Both form derivatives that effectively trap the cofactor precursor (uridine and adenine, respectively). Both may cause cirrhosis and tumors after repeated dosing. 

Differences Galactosamine causes diffuse hepatic necrosis, which is not zonal, whereas ethionine causes steatosis, which is initially periportal. 

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... 

Mechanism and Genetics of Induction in Mammals. Many different mechanisms may be involved in CYP induction. These include increased transcription of DNA, increased mRNA translation to protein, mRNA stabilization, and protein stabilization. Induction can only occur in intact cells and cannot be achieved by the addition of inducers directly to cell fractions such as microsomes. It has been known for some time that in most cases of increase in monooxygenase activity there is a true induction involving synthesis of new enzyme, and not the activation of enzyme already synthesized, since induction is generally prevented by inhibitors of protein synthesis. For example, the protein synthesis inhibitors such as puromycin, ethionine, and cyclo-heximide inhibit aryl hydrocarbon hydroxylase activity. A simplified scheme for gene expression and protein synthesis is shown in Figure 9.7. 

---