Explore chapters and articles related to this topic
Role of Metabolism in Chemically Induced Nephrotoxicity
Published in Robin S. Goldstein, Mechanisms of Injury in Renal Disease and Toxicity, 2020
The sulfoxide of DCVC is an extremely potent nephrotoxicant in rats, producing elevations in blood urea nitrogen concentrations and anuria while an equimolar dose of DCVC is not toxic (Sausen and Elfarra, 1990b). DCVC sulfoxide is also an extremely potent cytotoxicant in freshly isolated proximal tubular and distal tubular cells from rat kidney (Lash et al., 1994). In vivo, DCVC sulfoxide toxicity is specific to the kidneys, similar to the pattern found with DCVC, with no signs of hepatic injury being detected. Dependence of DCVC sulfoxide-induced nephrotoxicity in vivo and cytotoxicity in isolated renal cells on metabolism was demonstrated by showing that methimazole completely prevents injury (Sausen et al., 1992; Lash et al., 1994). AOAA has no effect on either DCVC sulfoxide-induced nephrotoxicity or cytotoxicity in cells, showing that the β-lyase is not involved in the bioactivation process. Although little is known about the mechanism of DCVC sulfoxide-induced nephrotoxicity and why DCVC sulfoxide is so much more potent than DCVC, the sulfoxide is a Michael acceptor that reacts with GSH and, therefore, possibly with other cellular macromolecules (Sausen and Elfarra, 1991). The sulfoxide is believed to spontaneously release a reactive sulfenic acid (Figure 14, pathway 7) that may be the ultimate toxic metabolite that forms covalent adducts in renal cells.
Evaluation of Anti-ulcer Potential of Sphenodesme involucrata var. paniculata (C.B. Clarke) Munir Leaves on Various Gastric Aggressive Factors
Published in Parimelazhagan Thangaraj, Phytomedicine, 2020
P. S. Sreeja, K. Arunachalam, Parimelazhagan Thangaraj
In addition, another class of drugs that was introduced include the proton pump inhibitors (inhibits H+, K+-ATPase pathway in parietal cells) represented by omeprazole, lansoprazole, rabeprazole, pantoprazole, and omeprazole. These drugs were considered as effective in minimizing acid secretion and cellular restitution during the treatment of gastric ulcers (Palileo and Kaunitz 2011). The process for decreasing acid in the gastric environment by these drugs occurs through the acid secretory canaliculi of the parietal cell. By this action, the inactivation of the proton pump occurs via the formation of disulfide bonds between the structure of the drugs and the protein structure of said pump. Its active form, cyclic sulfenamide or sulfenic acid, reacts by covalently binding to the sulfhydryl group of the proton pump extracellular domain cysteine, which enables the inhibition of the hydrochloric acid secretion. However, this type of drug therapy causes side effects, such as lower vitamin B12 and iron absorption, hypergastrinemia, thrombocytopenia, risk of pneumonia, headaches, nausea, weakness, diarrhea, and gastric cancer, as well as a greater susceptibility to bone fractures (Dacha et al. 2015; Singh et al. 2018).
The Modification of Cysteine
Published in Roger L. Lundblad, Chemical Reagents for Protein Modification, 2020
Cysteine is relatively sensitive to oxidation but there is little selectivity in these reactions. Mild oxidizing conditions can result in the formation of disulfide bonds with appropriately aligned cysteinyl residues. Formation of sulfenic acid is generally readily reversible unless stabilized by local conditions3 and more highly oxidized forms such as cysteine-sulfonic acid are more frequently observed. More rigorous conditions such as treatment with performic acid result in the formation of cysteic acid.
Phenylalanine 4-monooxygenase: the “sulfoxidation polymorphism”
Published in Xenobiotica, 2020
Stephen C. Mitchell, Glyn B. Steventon
Another fundamental problem is that the enzyme is generally regarded as a dioxygenase, attaching two oxygen atoms derived from molecular oxygen to form a sulfinic acid and not an unstable sulfenic acid. If it were to be involved in the metabolism of S-carboxymethyl-l-cysteine it would more likely produce a sulfone rather than a sulfoxide and trace amounts of the sulfone metabolite have only been reported once in human urine and may have been an artefact (Brockmoller et al., 1988). In general, compounds with a free sulfhydryl group are unable to form stable sulfenic acids, these compounds being transient intermediates that undergo disproportionation or self-condensation. To attain stability they require a polar or bulky grouping adjacent to the sulfenic acid moiety (Barrett, 1990; Hogg, 1990). With regards to cysteine, the sulfhydryl group needs to be substituted replacing the hydrogen atom with a more substantial moiety. S-carboxymethyl-l-cysteine is such a molecule with a carboxymethyl (–CH2COOH) entity being attached forming a thioether which may then produce a stable S-oxide. However, it is this addition to the cysteine molecule that presumably interferes with binding to the cysteine dioxygenase enzyme and moves the sulfur atom away from the catalytic site.
Irreversible oxidative post-translational modifications in heart disease
Published in Expert Review of Proteomics, 2019
Tamara Tomin, Matthias Schittmayer, Sophie Honeder, Christoph Heininger, Ruth Birner-Gruenberger
Addressing the reversible Cys reactions represents an ongoing challenge as free thiol residues are highly unstable and prone to artificial oxidation during sample preparation. In order to prevent post-sampling oxidation, most common approaches in redox proteomics involve initial blocking of free thiols with alkylating reagents such as iodoacetamide (IAA) or N-ethylmaleinimide (NEM) prior any further analytical steps [48]. Once all free thiols are blocked, higher oxidative states of Cys are either ‘trapped’ directly or selectively reduced back to free thiols and then subjected to a second alkylation step with isotopically and/or affinity-tag labeled alkylating reagents enabling enrichment and quantification of oxidized peptides. Another challenge when addressing reversible Cys oxPTMs is the stability of the given modification. For example, sulfenic acid, representing the initial step of Cys oxidation and an important modulator of protein function, is highly reactive and quickly interacting with surrounding amino acid residues, which makes sulfenylation a difficult modification to stabilize and detect. The speed of sample handling is of critical importance for sulfenic acid detection and the development of novel ‘trapping’ techniques, such as benzothiazine derivatives, is an ongoing effort [49,50]. For a better overview about specific methodologies for the analysis of reversible Cys modifications, we refer to Alcock et al. [50] and others [48,51].
Molecular effects of ozone on amino acids and proteins, especially human hemoglobin and albumin, and the need to personalize ozone concentration in major ozone autohemotherapy
Published in Critical Reviews in Clinical Laboratory Sciences, 2023
Fouad Mehraban, Arefeh Seyedarabi
A promising biomarker in systemic oxidative stress is glutathionylated Hb, which is formed as a result of the incubation and oxidation of Hb treated with H2O2 with physiological concentrations of GSH. This was found to occur via βCys93 and sulfenic acid intermediates [95]. Glutathionylated Hb can be formed at high concentrations of H2O2 that is produced by high concentrations of ozone [96], as well at high concentrations of GSH in RBCs [97].