Methionine toxicity

C37 Cox, R., Martin, J. T. and Shinozuka, H. Studies on acute methionine toxicity. II. Inhibition of ribonucleic acid synthesis in guinea pig liver by methionine and ethionine. Lab. Invest., 29, 54-59 (1973)... 

Detoxifica.tlon. Detoxification systems in the human body often involve reactions that utilize sulfur-containing compounds. For example, reactions in which sulfate esters of potentially toxic compounds are formed, rendering these less toxic or nontoxic, are common as are acetylation reactions involving acetyl—SCoA (45). Another important compound is. Vadenosylmethionine [29908-03-0] (SAM), the active form of methionine. SAM acts as a methylating agent, eg, in detoxification reactions such as the methylation of pyridine derivatives, and in the formation of choline (qv), creatine [60-27-5] carnitine [461-06-3] and epinephrine [329-65-7] (50). 

Arsenic. Arsenic is under consideration for inclusion as an essential element. No clear role has been estabHshed, but aresenic, long thought to be a poison, may be involved in methylation of macromolecules and as an effector of methionine metaboHsm (158,160). Most research has focused on the toxicity or pharmaceutical properties of arsenic (158). 

Although molybdenum is an essential element, excess levels can have deleterious effects. The LD q and TLV values of the most common Mo compounds are Hsted in Table 3 (63,64). In general the toxicity of Mo compounds is considered to be low. For example, M0S2 has been found to be virtually nontoxic even at high levels. Certain Mo compounds such as MoCl and Mo(CO), have higher toxicity because of the chemical nature and reactivity of these compounds rather than the Mo content. Supplementary dietary Cu ", thiosulfate, methionine, and cysteine have been shown to be effective in alleviating Mo toxicity in animals. 

There appear also to be toxic effects. In animals, nitrous oxide has been shown to inactivate methionine synthetase which prevents the conversion of deoxyuridine to thymidine and thus has the potential for inducing megaloblastic anemia, leukopenia, and teratogenicity (44—46). A variety of epidemiologic surveys suggest positive correlations between exposure to nitrous oxide and spontaneous abortion in dental assistants (47). 

Unfortunately, the modification of the side chain is not a generally applicable approach. Among the major, naturally occurring amino acids, only L-lysine has a chemically reactive side chain that would be as readily available for chemical modification as the side chain of glutamic or aspartic acid. Since, however, poly (L-lysine) is known to be toxic (10), its derivatives cannot be candidates for generally applicable biomaterials. Thus, most of the poly(amino acids) that have so far been suggested as biomaterials are derivatives of gluteunic or aspartic acid or copolymers of such derivatives with leucine, methionine, or a limited number of additional amino acids (11). 

Heinz, G.H., D.J. Hoffman, and L.J. LeCaptain. 1996. Toxicity of seleno-L-methionine, seleno-DL-methionine, high selenium wheat, and selenized yeast to mallard ducklings. Arch. Environ. Contamin. Toxicol. 30 93-99. 

Most published examples of prodrugs of relevance in the present context contain an a-amino acyl moiety. A number of reasons may explain this fact, such as the lack of toxicity of these natural compounds, the large differences in lipophilicity and other properties between amino acids, and the variability afforded by A-substituents. Interesting examples are provided by salicylic acid and metronidazole. Thus, the hydrolysis of tyrosine and methionine prodrugs of salicylic acid (8.104 and 8.105, respectively) was examined in rabbits after intraduodenal and intracecal administration [134], The former ester, but not the latter, was hydrolyzed in the mucosa of the small intestine. In addition, both prodrugs underwent marked hydrolysis by intestinal microflora. 

A high level of homocysteine is an indication of a low rate of conversion of homocysteine to methionine and hence a low level of the methylating agent S-adenosyl methionine. The latter, plus the toxic effects of homocysteine, provides a link between the reactions listed above and three diseases cardiovascular disease (Chapter 22), senile dementia (Chapter 14) and cancer (Chapter 21). 

The biological role of PIMT involves the selective methylation of isoaspartate residues followed by a demethylation step to reform the succi-nimide intermediate. The demethylation causes the release of methanol which can be converted to formaldehyde and finally to formic acid, as demonstrated in rat brain preparations. It was found that S-adenosyl-methionine (SAM), the methyl donor, caused formaldehyde levels to rise in the rat brain homogenates, thus suggesting that excessive formaldehyde may be a precipitating factor in Parkinsons s disease (PD) (Lee et ah, 2008). It is possible that carnosine could suppress formaldehyde toxicity by reacting with it to generate a carnosine-formaldehyde adduct. This should be a relatively easy experiment to perform to test this prediction. 

Milazzo, L, Piazza, M., Sangaletti, O., Gatti, N., Cappelletti, A., Adorni, F., Antinori, S., Galli, M., Moroni, M. and Riva, A. (2005) [13C]Methionine breath test a novel method to detect antiretroviral drug-related mitochondrial toxicity. Journal of Antimicrobial Chemotherapy, 55 (1), 84—89. 

Nutritional status can also influence the toxic potency of carbon tetrachloride. Animal studies have clearly demonstrated that brief fasting or consumption of diets low in antioxidants (vitamin E, selenium, methionine) can lead to increased carbon tetrachloride hepatotoxicity. The same may be true for humans, although this is not known for certain. Another aspect of nutritional status affecting carbon tetrachloride toxicity is hepatic energy status. Hepatic ATP levels might influence the ultimate outcome of toxicity (low levels may inhibit recovery mechanisms). 

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