The Role of Glutathione in Detoxication

Abstract

Glutathione (GSH) is a strong nucleophile which reacts well with soft electrophiles, but poorly with both weak and strong electrophiles. Weak electrophiles have low reactivity with all nucleophiles while strong electrophiles react well with weak nucleophiles including superabundant H20.There are enzymes, the GSH transferases, which catalyze GSH conjugation with all the types of electrophiles described above. In order to deal with the wide variety of potential substrates, a multiplicity of GSH transferases exists-each tissue having its own collection and each enzyme having a different substrate specificity. These enzymes are often very abundant, e.g., in the rat liver cytosol, their concentration is 0.2 mM.The following substrates are considered in some detail: 1-chloro-2,4-dinitrobenzene, the electrophile derived metabolically from paracetamol N-acetyliminoquinone?), benzo(a)pyrene-4-5-oxide, cholesterol-5a,6a-oxide, benzo(a)pyrene-7,8-diol-9,10-oxide and the electrophiles derived metabolically from aflatoxin B, (the 2,3-oxide?). According to the substrate, optimal enzyme rates vary over seven orders of magnitude from 10-1 to 10-12 mole/min/mg.Despite the wide embrace of the GSH transferases, not all metabolically produced electrophiles are substrates. We know of the following examples: N-methylol-4-aminoazobenzene and its 4'-hydroxy derivative (these are soft electrophiles and react well with GSH noncatalytically), N-sulfonyloxy-N-methyl-4-aminoazobenzene, N-sulfonyloxy-N-acetyl-2-aminofluorene (these are strong electrophiles which do not react selectively with GSH) and N-hydroxy-2-aminofluorene which appears to react only slowly with GSH. It is of interest in the present context that all these compounds are derived from either arylamine or arylamide carcinogens.Whether the reaction be enzymic or nonenzymic, conjugation with GSH is a very important means of detoxication accounting in some cases for up to 60% of the biliary metabolites. As seen in the example of aflatoxin B,, very low enzymic rates observed in vitro are sufficient to account for apparently high rates of biliary excretion of GSH conjugates.GSH transferases have evolved other functions apart from the catalysis of GSH conjugation. GSH transferase B participates in the hepatic uptake of bilirubin and the intracellular distribution of the heme prosthetic group. It also has GSH peroxidase activity which suggests that it might participate in the detoxication of by-products of oxygen utilization including those produced by the action of cytochrome P-450. It is shown that GSH transferase B inhibits lipid peroxidation in vitro. GlutathioneGlutathione (GSH), y-glutamylcysteinylglycine, is a molecule with the following important properties. Its cysteinyl residue provides a nucleophilic thiol important for the detoxication of electrophilic metabolites and metabolically produced oxidizing agents. Its net negative charge and overall hydrophilicity greatly increases the aqueous solubility of the lipophilic moieties with which it becomes conjugated. Its molecula...

Quantitatively evaluating detoxification of the hepatotoxic microcystin-LR through the glutathione (GSH) pathway in SD rats

“…Glutathione (GSH), the most abundant non-protein thiol present mainly in liver, was confirmed to play crucial roles in antioxidant defense and detoxification metabolism of many xenobiotics (Ketterer et al 1983;Lu 2013). Microcystins (MCs) are known as hepatotoxins since liver of animals (both aquatic animals and mammals) is the most important target organ (Clark et al 2007;Malecot et al 2011).…”

Quantitatively evaluating detoxification of the hepatotoxic microcystins through the glutathione and cysteine pathway in the cyanobacteria-eating bighead carp

“…It is well known that GSH plays a significant role in the metabolism of xenobiotics, and its conjugation with xenobiotics is considered as an important metabolic pathway for detoxification (Ketterer et al, 1983). GSH can conjugate with MC-LR via glutathione-S-transferase in various aquatic macrophyte, invertebrates, fish eggs and fish, and subsequently degraded to MCLR-Cys (Carmichael, 1992;Dittmann and Wiegand, 2006;Pflugmacher et al, 1998).…”

Expression profiles of seven glutathione S-transferase (GST) genes from Venerupis philippinarum exposed to heavy metals and benzo[a]pyrene

“…Therefore, changes in VpGSTs expression observed in V. philippinarum exposed to B[a]P indicated that VpGSTs may have a defensive role against B[a]P toxicity. As an important phase II biotransformation enzyme, GSTs catalyze the conjugation of the glutathione (GSH) to electrophilic xenobiotics and oxidized components in order to increase their hydrophilicity and facilitate the excretion of toxicants (Ketterer et al, 1983).…”

“…Generally, the detoxification mechanisms of GSTs lie in the conjugation of reduced glutathione with toxic compounds or their metabolites to increase the hydrophilicity and facilitate the excretion of toxicants (Ketterer et al, 1983). Moreover, GSTs have been found to play a critical role in mitigating oxidative stress in all life forms (Lee et al, 2008), and GST activities have been widely used as potential biomarkers for the monitoring of environmental pollution as well (Hoarau et al, 2002;Shailaja and D'Silva, 2003;Cunha et al, 2007).…”