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Biochemical Methods of Studying Hepatotoxicity
Published in Robert G. Meeks, Steadman D. Harrison, Richard J. Bull, Hepatotoxicology, 2020
Prasada Rao S. Kodavanti, Harihara M. Mehendale
Changes in GSH and related disulfide levels can be elicited by several toxic stimuli to cells. These effects can be conveniently studied using isolated cells or organs and are good models to study several electrophilic or radical-producing chemicals. Menadione is one of such compounds that has been studied for its ability to oxidize GSH in isolated liver perfusion experiments. The changes in GSH are accompanied by other cytotoxic changes such as altered Ca2+ transport in hepatocytes (Mehendale et al., 1985). The phase II conjugation system has been reported to be induced by phenobarbital (Utley and Mehendale, 1989). Some studies, specifically involving GSH metabolism in isolated cells or organ perfusions, where serum or albumin are supplemented in the medium, are complicated because of the ability of GSH to bind to albumin and ultimately get oxidized (Joshi et al., 1986, 1987, 1988). Therefore, special care should be taken while interpreting the results. Next, we discuss the enzymes of glutathione metabolism.
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 is synthesized from its constituent amino acids and broken down via the γ-glutamyl cycle. The synthesis of GSH is catalyzed by γ-glutamylcysteine synthetase and glutathione synthetase, the former being the rate-limiting enzyme. The activity of both enzymes is under substrate and product (feedback) control. GSH is oxidized to GSSG by GSH peroxidase, and GSSG is reduced to GSH by glutathione reductase. The breakdown of glutathione is catalyzed by γ-glutamyl transferase, a membrane-bound enzyme that catalyzes the transfer of the γ-glutamyl moiety to free amino acids. γ-Glutamyl dipeptides are then split by γ-glutamyl cyclotransferase into its constituent amino acids and 5-oxoproline. The latter is further metabolized to glutamate by 5-oxoprolinase (Meister and Anderson 1983; Deneke and Fanburg 1989). The cellular and regional distribution of the enzymes involved in glutathione metabolism parallels that of glutathione (Philbert et al. 1991).
The thiols glutathione, cysteine, and homocysteine in human immunodeficiency virus (HIV) infection
Published in Ronald R. Watson, NUTRIENTS and FOODS in AIDS, 2017
F. Müller, P. Aukrust, A.M. Svardal, R.K. Berge, P.M. Ueland, S.S. Frøland
Liver is an important source of extracellular glutathione.31 Plasma glutathione is used by many tissues which have high levels of γ-glutamyl transpeptidase, e.g., kidney, lung, and brain.30 Glutathione itself is not transported into most of the cells of these tissues, but is broken down by the membrane-bound-γglutamyl transpeptidase and dipeptidases, and the breakdown products are transported and utilized for glutathione synthesis. This is an important pathway of glutathione metabolism.26,28,30 Thus, γ-glutamyl transpeptidase is not only important in the breakdown of glutathione, but also in preventing loss of thiol moieties and in the transport of glutathione precursors into cells.
Purification and characterisation of glutathione reductase from scorpionfish (scorpaena porcus) and investigation of heavy metal ions inhibition
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2023
Glutathione reductase (EC 1.8.1.7; GR), a major enzyme in glutathione metabolism, is required for the maintenance of the reduced form of cellular glutathione, which is strongly nucleophilic for many reactive electrophiles10,11. The flavin enzyme GR acts as an antioxidant to protect cells from oxidative stress by reducing glutathione disulphide (GSSG) to its reduced form (GSH)12. It has an important role in the drug and detoxification mechanisms especially in the liver. This is due to the cytochrome P-450 system found in liver microsomes, which provides detoxifying events13. Maintaining the GSH/GSSG ratio in the cell environment is one of the most important known targets of the GR enzyme-catalysed reactions14. Glutathione reductase is involved in the reduction-oxidation of intracellular glutathione for GSSG, which is generated through the detoxification of hydroperoxides and reduction of some other chemicals catalysed by glutathione perdoxidase15. The NADP+ dependent malate dehydrogenase and pentose phosphate pathways provide the NADPH needed in this catalytic process16,17. NADPH, a key product of the pentose phosphate cycle, is employed extensively in reductive biosynthesis. Furthermore, it aids in the protection of the cell against oxidative damage9.
Metabolomic markers predictive of hepatic adaptation to therapeutic dosing of acetaminophen
Published in Clinical Toxicology, 2022
Brandon J. Sonn, Kennon J. Heard, Susan M. Heard, Angelo D’Alessandro, Kate M. Reynolds, Richard C. Dart, Barry H. Rumack, Andrew A. Monte
Using pre-treatment samples, this study has identified a combination of clinical chemistry and metabolomic biomarkers that are predictive of subjects who will develop transient ALT elevation and subsequent hepatic adaptation. In this study, the adaptation cohort was defined as having a transiently elevated ALT when APAP therapy was administered at maximum recommended therapeutic dosing for 16 consecutive days. Biomarkers and biological pathways were identified for subjects who required hepatic adaptation. The metabolome observed in pre-treatment samples suggests alterations in the glutathione metabolism and the urea cycle associated with hepatic adaptation. These alterations may be indicative of underlying mitochondrial dysfunction, leading to ALT elevation and subsequent hepatic adaptation.
Chondrocyte protein co-synthesis network analysis links ECM mechanosensing to metabolic adaptation in osteoarthritis
Published in Expert Review of Proteomics, 2021
Aspasia Destouni, Konstantinos C. Tsolis, Anastassios Economou, Ioanna Papathanasiou, Charalampos Balis, Evanthia Mourmoura, Aspasia Tsezou
Integration of phospholipid hydroperoxide glutathione peroxidase 4 (GPX4) connected the proteins involved in glutathione metabolism (glutathione S-transferase Mu 2 [GSTM2], glutathione S-transferase Mu 3 [GSTM3] and glutathione synthetase [GSS]) to the core interactome, which remained unconnected in the healthy network (Figure 4a, Figure 5a). GPX4 is a key enzyme that reduces phospholipid hyperoxides to alcohols and protects cells from ferroptosis [50], a process of cell death. A cell density-induced adaptive mechanism rescues cells from the lipotoxic conditions by sequestering poly-unsaturated fatty acid (PUFA) TGAs in lipid droplets (LDs) protecting cells from ferroptosis [51]. Lysophosphatidylcholine acyltransferase 1 (LPCAT1), one of the Lands cycle key enzymes, responsible for phospholipid remodeling at membranes, was exclusive to the OA interactome. LPCAT1 has been found to localize to the phosphatidylcholine (PC) monolayer membrane of the neutral triacylglycerol (TGA) containing lipid droplet (LD) [52].