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Glutathione and Glutathione Derivatives: Possible Modulators of Ionotropic Glutamate Receptors
Published in Christopher A. Shaw, Glutathione in the Nervous System, 2018
Réka Janáky, Vince Varga, Zsolt Jenei, Pirjo Saransaari, Simo S. Oja
Glutathione (Reichelt and Fonnum 1969; Slivka et al. 1987a,b; Kirstein et al. 1991), S-methylglutathione (SMG) (Kanazawa et al. 1965), and glutathione sulfonate (GSA) (Li et al. 1993b) are endogenous constituents of brain tissue. The total level of glutathione in the CNS is within the range of 1.4–3.4 mM. The greater part of glutathione (about 95 percent) is in reduced form (Slivka et al. 1987b), but under oxidizing conditions GSSG may be present at higher concentrations (Folbergrova, Rehncrona, and Siesjö 1979). The concentration of SMG is 0.1–0.2 mg per kilogram of fresh brain tissue. SMG was the first example to be recognized of an occurrence of S-methylcysteine in a peptide (Kanazawa et al. 1965).
A Review of Epidemiologic Studies with Regard to Routes of Exposure to Toxicants
Published in Rhoda G. M. Wang, James B. Knaak, Howard I. Maibach, Health Risk Assessment, 2017
Since hemoglobin adducts have the same biological life span as hemoglobins in blood, they can provide a better index of recent exposure (including intermittent exposure) than measurements of metabolites in blood and urine. Methyl bromide has been shown to react with cysteine to form methylcysteine in hemoglobin. Studies of 14 methyl bromide workers suggested that methylcysteine (MeCys) in hemoglobin was a biological exposure index.39 Oral and inhalation exposures to three monohalomethanes (methyl bromide, methyl chloride, and methyl iodide) in rats showed highest binding to hemoglobin for methyl bromide, and higher binding via the inhalation vs. the oral route.40 These studies suggest that hemoglobin adducts should be explored further in human studies, including epidemiologic studies involving exposure to monohalomethanes. The genotoxic potential of certain monohalomethanes supports the need for such studies.
Analysis of Modified Amino Acids
Published in Ajit S. Bhown, Protein/Peptide Sequence Analysis: Current Methodologies, 1988
Since the last comprehensive compilation in 1980,9 the number of proteins which have been reported to contain methylated amino acid residues has steadily grown. We, therefore, updated the original list. Table 1 lists 20 additional new references; they include proteins such as α-amylase, HMG-1 and HMG-2 proteins, nuclear acidic phosphoprotein C-23, citrate synthase, elongation factors, initiation factor, and heat shock proteins. Also included are newly observed amino acids such as S-methylmethionine, S-methylcysteine, and δ-N-methylarginine.
Phenylalanine 4-monooxygenase: the “sulfoxidation polymorphism”
Published in Xenobiotica, 2020
Stephen C. Mitchell, Glyn B. Steventon
Of the few compounds shown to be substrates, S-methyl-l-cysteine has been reported as having anti-lipidaemic properties (Hasimun et al., 2011) and attenuating metabolic syndrome, inflammation and oxidative stress in the rat (Thomas et al., 2015) as well as use as adjunctive therapy in obviating Parkinson’s-like symptoms (Wassef et al., 2007). Studies in healthy volunteers have shown widespread biotransformation of this compound with indications of variation in sulfoxide output, but the numbers involved were far too small for any meaningful inferences to be drawn (Mitchell et al., 1984a). The sulfoxide metabolite also possesses several therapeutic attributes (Edmands et al., 2013) but it appears not to have been exploited. The l-cysteine methylester, often confusingly termed “methylcysteine” or “mecysteine”, has been used as a mucolytic but it is doubtful that, possessing a free thiol group, it would be acted upon by phenylalanine 4-monoxygenase.
Toxicity mechanism-based prodrugs: glutathione-dependent bioactivation as a strategy for anticancer prodrug design
Published in Expert Opinion on Drug Discovery, 2018
Xin-Yu Zhang, Adnan A. Elfarra
Once inside renal cells, DCVC can undergo further metabolism to be converted to reactive electrophiles [34], causing toxicity. Specifically, nephrotoxicity of DCVC has been attributed to two bioactivation pathways. In one pathway, DCVC undergoes a β-elimination reaction catalyzed by pyridoxal 5′-phosphate-dependent β-lyases to generate four reactive electrophiles: chlorothioketene (CTK), 2-chlorothionoacetyl chloride (2-CTA), and their corresponding hydrolysis products chloroketene (CK) and 2-chloroacetyl chloride (2-CA) [31,39]. Pretreatment of rats with aminooxyacetic acid (AOAA), a selective inhibitor of β-lyases, reduced nephrotoxicity of DCVC; S-(1,2-dichlorovinyl)-DL-α-methylcysteine, which cannot be cleaved by β-lyases, was not nephrotoxic [37,38,40,41], providing evidence for this pathway. The second pathway implicated in DCVC nephrotoxicity is the oxidation mediated by flavin-containing monooxygenase 3 (FMO3) [42–44], which leads to the formation of S-(1,2-dichlorovinyl)-L-cysteine sulfoxide (DCVCS; Figure 1), a highly reactive Michael acceptor [45]. In rats, the AOAA pretreatment did not protect against DCVCS nephrotoxicity but partly protected against DCVC nephrotoxicity [45], providing evidence for the in vivo presence of the two pathways.