5- Methyl-glutathione

Glutathione S-transferases are important in the metabolism of organophosphorus insecticides resulting in detoxification. For example, methyl parathion is dealkylated by glutathione S-transferase to form desmethyl parathion and methyl glutathione (Figure 8.21). 

A. Methyl bromide is a potent nonspecific alkylating agent with a special affinity for sulfhydryl and amino groups. Limited data indicate that toxicity is either the result of direct alkylation of cellular components (eg, glutathione, proteins, or DNA) or formation of toxic metabolites from methylated glutathione. Animal data clearly indicate that its toxicity does not result from the bromide ion. 

B. Specific drugs and antidotes. Theoretically, /V-acetylcysteine (NAC, p 405) or dimercaprol (BAL, p 413) can offer a reactive sulfhydryl group to bind free methyl bromide, although neither agent has been critically tested. Some data suggest that toxicity may be due to toxic metabolites formed from methylated glutathione If this Is true then NAC could possibly exacerbate toxicity. Neither agent can be recommended at this time. 

Defoy, D., Dansette, P.M., Neugebauer, W., Wagner, J.R., Klarskov, K. (2011) Evaluation of Deuterium Labeled and Unlabeled Bis-methyl Glutathione Combined with Nanoliquid Chromatography-Mass Spectrometry to Screen and Characterize Reactive Drug Metabolites. Chem. Res. Toxicol. 24 412-417. 

For the biosynthesis of iS-methyl cysteine sulfoxide, methyl donor can be methionine because the radioactively labeled methionine could be incorporated into the S-methyl cysteine and iS-methyl cysteine sulfoxide (Sugii et al. 1963 Granroth 1970) (Figure 18.3). Regarding the S-methyl glutathione was detected in garlic (Lancaster and Shaw 1989 ... 

Williams PAM, Baran EJ. 1994. The interaction of the cation with S-methyl-glutathione. JInorgBiochem 54 75-78. 

Acetaminophen, which depletes hepatic glutathione, does not potentiate the toxicity of methyl parathion in mice. A possible mechanism of action may be competition between acetaminophen and methyl parathion for mixed function oxidases and subsequent prevention of activation of methyl parathion to methyl paraoxon (Costa and Murphy 1984). Diethyl maleate, an agent that depletes cytosolic glutathione and is not an enzyme inducer, potentiates toxicity of methyl parathion in mice (Mirer et al. 1977). 

Huang YS, Sultatos LG. 1993. Glutathione-dependent biotransformation of methyl parathion by mouse liver in vitro. Toxicol Lett 68 275-284. 

Radulovic LL, Kulkami AP, Dauterman WC. 1987. Biotransformation of methyl parathion by human foetal liver glutathione S-transferases An in vitro study. Xenobiotic 17 105-114. 

Radulovic LL, Laferla JJ, Kulkami AP. 1986. Human placental glutathione S-transferase-mediated metabolism of methyl parathion. Biochem pharmacol 35 3473-3480. 

Sultatos LG, Woods L. 1988. The role of glutathione in the detoxification of the insecticides methyl parathion and azinphos-methyl in the mouse. Toxicol Appl Pharmacol 96 168-174. 

Sultatos LG, Huang GJ, Jackson O, et al. 1991. The effect of glutathione monoethyl ester on the potentiation of the acute toxicity of methyl parathion, methyl paraoxon or fenitrothion by diethyl maleate in the mouse. Toxicol Lett 55 77-83. 

Residues of PCBs in animal tissues include not only the original congeners themselves, but also hydroxy metabolites that bind to cellular proteins, for example, transthyretin (TTR Klasson-Wehler et al. 1992 Brouwer et al. 1990 Fans et al. 1993). Small residues are also found of methyl-sulfonyl metabolites of certain PCBs (Bakke et al. 1982, 1983). These appear to originate from the formation of glutathione conjugates of primary epoxide metabolites, thus providing further evidence of the existence of epoxide intermediates. Further biotransformation, including methylation, yields methyl-sulfonyl products that are relatively nonpolar and persistent. 

In phase 2, the hydroxylated or other compounds produced in phase 1 are converted by specific enzymes to various polar metabohtes by conjugation with glucuronic acid, sulfate, acetate, glutathione, or certain amino acids, or by methylation. 

Han, QP and Dryhurst, G (1996) Influence of glutathione on the oxidation of l-methyl-6-hydroxy-l,2,3,4-tetrahydro-beta-carboline chemistry of potential relevance to the addictive and neurodegenerative consequences of ethanol use. J. Med. Chem. 39 1494-1508. 

Thiols are also important protection against lipid peroxidation. Glutathione (7-Glu-Cys-Gly) is used by several glutathione-dependent enzymes such as free-radical reductase (converts vitamin E radical to vitamin E), glutathione peroxidase (reduces hydrogen peroxide and lipid hydroperoxides to water and to the lipid alcohol, respectively), and others. In addition, the thiol group of many proteins is essential for function. Oxidation of the thiol of calcium ATPases impairs function and leads to increased intracellular calcium. Thiol derivatives such as the ovothiols (l-methyl-4-mercaptohistidines) (Shapiro, 1991) have been explored as therapeutics. 

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