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PubMed1977

Stability of commonly used thiols and of human creatine kinase isoenzymes during storage at various temperature in various media.

We assessed the stability--at 20, 4 --20, and --80 degrees C--of 2-mercaptoethanol, dithioerythritol, and dithiothreitol, and of semi-purified creatine kinase isoenzymes of human origin in the presence and absence of the three compounds. The isoenzymes plus the sulfhydryl compounds were also assessed an aqueous buffer, in heat-inactivated pooled sera, or in fresh pooled sera with low endogenous total creatine kinase. We also examined the influence of thawing conditions from--20 or--80 degrees C, of fast freezing, and of exposure to fluorescent light. At 20 and 4 degrees C some--SH groups are oxidized. At--20 and--80 degrees C this loss is diminished. It is a function of both temperature and diluent. For stability, creative kinase isoenzymes stored at any temperature require the presence of a suitable sulfhydryl compound. Periodic addition of fresh sulfhydryl solutions stabilized creatine kinase isoenzymes suspended in the two protein-based diluents by 10-30%; for those in an aqueous buffer such additions decreased the activity to stored creatine kinase isoenzymes. Fast freezing does not increase recovery of creatine kinase isoenzyme activity over slow freezing at--80 or--20 degrees C. Thawing should be done as infrequently as possible and should be done rapidly, at 37 degrees C, for the residual enzyme activity to be maximal.

Creatine Kinase↗
PubMed1999

The sulfhydryl containing compounds WR-2721 and glutathione as radio- and chemoprotective agents. A review, indications for use and prospects.

Radio- and chemotherapy for the treatment of malignancies are often associated with significant toxicity. One approach to reduce the toxicity is the concomitant treatment with chemoprotective agents. This article reviews two sulfhydryl compounds, namely the agent WR-2721 (amifostine), a compound recently registered for use in human in many countries, and the natural occurring compound glutathione (GSH). GSH is not registered as a chemoprotective agent. WR-2721 is an aminothiol prodrug and has to be converted to the active compound WR-1065 by membrane-bound alkaline phosphatase. WR-1065 and GSH both act as naturally occurring thiols. No protective effect on the tumour has been found when these compounds are administered intravenously. There is even in vitro evidence for an increased anti-tumour effect with mafosfamide after pretreatment with WR-2721, and in vivo after treatment with carboplatin and paclitaxel. Randomized clinical studies have shown that WR-2721 and GSH decrease cisplatin-induced nephrotoxicity and that WR-2721 reduces radiation radiotherapy-induced toxicity. Side-effects associated with WR-2721 are nausea, vomiting and hypotension, GSH has no side-effects. An exact role of WR-2721 and GSH as chemoprotectors is not yet completely clear. Future studies should examine the protective effect of these drugs on mucositis, cardiac toxicity, neuro- and ototoxicity, the development of secondary neoplasms and their effect on quality of life.

Amifostine↗
PubMed1991

Biochemical and pharmacological interactions between nitroglycerin and thiols. Effects of thiol structure on nitric oxide generation and tolerance reversal.

Co-administration of N-acetylcysteine (NAC) with nitroglycerin (NTG) has been shown to partially reverse nitrate tolerance and to potentiate the hypotensive effect of NTG in humans. However, a high clinical dose of NAC was required for this pharmacologic interaction resulting in the production of unwanted side-effects. Therefore, sulfhydryl compounds more active than NAC need to be identified if this interaction is to be exploited clinically. We previously suggested that the effect of sulfhydryl compounds on NTG may be mediated by the formation of S-nitrosothiol or nitric oxide (NO) extracellularly to the vascular smooth muscle cell (e.g. in plasma) (Fung et al., J. Pharmacol Exp Ther 245: 524-530, 1988). In an attempt to understand the structural features which govern this thiol-catalyzed NO generation from NTG, nineteen different aliphatic and ten aromatic sulfhydryl compounds were examined with respect to their catalytic activity to generate NO from NTG in plasma. Significantly enhanced production of NO was observed with most sulfhydryl compounds examined when compared to buffer control. Among the aliphatic thiols, only mercaptosuccinic acid was more potent than NAC (2x), whereas among the aromatic thiols, both thiosalicylic acid (TSA, 10x) and TSA-methyl ester (3x) were more potent than NAC. Comparative in vitro relaxation studies were carried out using isolated (and nitrate-tolerant) rat aortic rings with NTG/TSA and NTG/NAC, in the presence of 0.5% (v/v) plasma. Under these conditions, partial reversal of NTG tolerance could be achieved with TSA, but not with NAC. These data are consistent with the view that extracellular production of NO or S-nitrosothiol serves as a tolerance-reversing mechanism of thiols on NTG. TSA appears to be a more potent sulfhydryl compound than NAC in this biochemical and pharmacologic interaction.

Acetylcysteine↗
PubMed1977

The role of sulfhydryl groups in the binding of glucocorticoids by cytoplasmic receptors of lung and other mammalian tissues.

We examined the levels and stability of glucocorticoid receptor activity in cytosol preparations of rat lung and other tissues. [3H]Dexamethasome binding capacity at 2 C in lung cytosol decreases with a t1/2 of 40 min in the absence of steroid or a sulfhydryl compound. This rapid inactivation of unbound receptor is prevented and reversed by addition of a sulfhydryl compound (t1/2 = 22h); maximal binding occurs with 2 mM dithiothreitol (DTT), or with 20-25 mM mercaptoethanol, thioglycerol or glutathione. Binding activity is also stabilized by formation of the receptor-steroid complex; dissociation of the complex occurs at the same rate (t1/2 = 18.6h) in both the presence and absence of DTT. In the presence of DTT, cytosol of adult rat lung specifically binds 0.82 pmol of [3H]dexamethasone per mg protein (average 19,000 sites per cell) with an equilibrium dissociation contant of 2.5 nM at 2 C. At 37 C, dispersed lung cells show specific nuclear binding of hormone. DTT also increased dexamethasone binding activity in cytosol prepared from lung of adult hamster, adult mouse, fetal monkey and 11 of 15 tissues of adult rat. There was a minimal effect of DTT in reactions using cytosol of fetal rat lung, fetal and newborn human lung, rabbit lung, and liver, kidney, heart and testis of adult rat. Liver contains a heat-stable factor which mimics that stabilizing effect of DTT. The variable requirement for DTT may reflect in part tissue concentrations of endogenous sulfhydryl compounds. Our findings indicate that glucocorticoid binding activity of lung and many other tissues decays rapidly in vitro due to oxidation of receptor sulfhydryl groups. Maintenance of these groups in the reduced form by endogenous tissue factors, addition of sulfhydryl compounds, or binding of glucocorticoid stabilizes receptor and allows its detection in lung and other tissues previously found to contain little if any activity.

Adrenalectomy↗
PubMed1989

1-p-chlorophenyl-4,4-dimethyl-5-diethylamino-1-penten-3-one hydrobromide, a sulfhydryl-specific compound which reacts irreversibly with protein thiols but reversibly with small molecular weight thiols.

1-p-Chlorophenyl-4,4-dimethyl-5-diethylamino-1-penten-3-one hydrobromide (CDDP) has been shown to react selectively with small molecular weight and protein thiols. The reaction of this compound with thiols can be monitored directly owing to the large decrease (approximately 21,000 M-1 cm-1 at 310 nm) in extinction coefficient subsequent to thiol addition. CDDP reacted stoichiometrically with large molecular weight (greater than 11,000) protein thiols. However, with small molecular weight thiols (less than 500) the reaction was less than stoichiometric, indicating a significant degree of back-reaction. The forward and reverse rate constants have been estimated. The fact that the reaction is reversible enables CDDP to be used for the direct monitoring of the oxidation of small molecular weight thiols.

Chlorobenzenes↗
PubMed1996

Mechanisms for cytoprotection by vitamin U from ethanol-induced gastric mucosal damage in rats.

A comparison was made of the effects of a nonsulfhydryl compound, vitamin U (methylmethioninesulfonium chloride, MMSC), and a sulfhydryl compound, cysteine (Cys), with regard to the inducement of acute gastric mucosal damage in the presence and absence of N-ethylmaleimide (NEM), a sulfhydryl-blocking reagent. The effects of MMSC, Cys, or NEM on gastric mucin content were examined using a newly developed biochemical method. MMSC and Cys inhibited mucosal damage due to 50% ethanol. The preinjection of NEM had no effect on cytoprotection of prostaglandins, but prevented the effects of Cys and MMSC. MMSC and Cys increased surface mucin content but lessened that of deep mucin. NEM decreased surface mucin and increased deep mucin. It thus follows that sulfhydryl compounds accelerate the secretion of deep mucin and accumulate surface mucin. The cytoprotective mechanism of MMSC may thus be mediated by sulfhydryl compounds, and the increase in surface mucosal mucin may possibly be related to cytoprotection.

Animals↗
PubMed1987

Histochemical evaluation of glutathione in brain.

Glutathione (GSH) is a ubiquitous cellular sulfhydryl compound with a variety of essential functions. A histochemical method that was developed by others for the localization of GSH in tissue sections was used to study the localization of GSH in rodent and primate brain. Sections of freshly frozen tissue were stained for 4 min with Mercury orange dissolved in toluene, and viewed by fluorescence microscopy for the product of the reaction with soluble sulfhydryl compounds. Soluble sulfhydryl compounds are comprised almost exclusively of GSH. Although the brain exhibits strong staining characteristics, reflecting the millimolar levels of GSH that are detected by chemical assay, very little stain is seen in neuronal somata. Pretreatment of animals with diethyl maleate resulted in depletion of GSH from brain (measured by high performance liquid chromatography), as well as decreased Mercury orange staining. The staining pattern observed in the brain may indicate that GSH is primarily localized to non-neuronal elements, such as glia, and/or in axons and nerve terminals.

Animals↗
PubMed1997

Cigarette smoke extract inhibits plasma paraoxonase activity by modification of the enzyme's free thiols.

Cigarette smoking is associated with an increased incidence of premature atherosclerosis. Minimal information is available at the molecular level concerning the mechanism of action of cigarette smoke. Recent work has shown that paraoxonase (PON) protects low density lipoprotein against oxidation by Cu2+. The goal of the present study was to investigate the effect of cigarette smoke extract (CSE) on human plasma paraoxonase activity. The activity of paraoxonase was inhibited by the CSE in a dose- and time-dependent manner. The inhibition of PON activity by the CSE was reversed by the addition of glutathione or N-acetyl cysteine. Furthermore, we tested to see whether sulfhydryl compounds prevented the inhibition of PON activity caused by CSE. Sulfhydryl compounds prevented the inhibition of PON activity caused by CSE. But any amino compounds, such as N-acetyl lysine, N-acetyl arginine and aminoguanidine, failed to protect PON activity, indicating a specificity with regard to the ability of free thiols to buffer the deleterious components of CSE which inhibited PON activity. The observed inhibition of PON activity by CSE may account for the increased incidence of cardiovascular disease known to be present in smokers through the oxidative process of low density lipoprotein and its subsequent uptake by macrophage.

Aryldialkylphosphatase↗
PubMed1980

Effects of ergothioneine, cysteine, and glutathione on nitrosation of secondary amines under physiologic conditions.

The effects of ergothioneine, cysteine, and glutathione, which are naturally occurring sulfhydryl compounds, on the aerobic and anaerobic nitrosation of dimethylamine were studied at pH 2.0-7.0 and at 37 degrees C. Under aerobic conditions, ergothioneine increased the formation of dimethylnitrosamine (DMN) at all pH values tested, cysteine and glutathione had the same effect at pH 4.0-6.0, and cysteine formed DMN at pH 7.0. However, as compared to controls cysteine showed no increased effect in an O2 atmosphere at pH 6.0. The effects of sulfhydryl compounds on anaerobic nitrosation were more significant (p < 0.001) than on aerobic nitrosation, probably because these sulfhydryl compounds, except ergothioneine, are easily oxidized. Ergothioneine increased aerobic nitrosation almost as strongly as anaerobic nitrosation. The effects of sulfhydryl compounds, especially ergothioneine, on nitrosation at physiologic pH and temperature might be significant in the in vivo formation of N-nitrosamines in the hemorrhage or ulcerous gastrointestinal tract or injured organs.

Animals↗
PubMed1985

Involvement of protein sulfhydryls in the trigger reaction of rhodotorucine A, a farnesyl peptide mating pheromone of Rhodosporidium toruloides.

The involvement of protein sulfhydryls for the signaling of rhodotorucine A, a mating pheromone produced by mating type A cells of Rhodosporidium toruloides, was investigated by the use of sulfhydryl compounds. The sulfhydryl-blocking reagent 5,5'-dithiobis(2-nitrobenzoic acid) (DTNB; Ellman's reagent) strongly inhibited both the biological effect of the pheromone on the recipient cell and the hydrolysis of the pheromone, which is catalyzed by the mating type-specific surface endopeptidase of the recipient cell. Conversely, the two reactions were markedly enhanced by the presence of the reducing reagent dithiothreitol. The inhibitory effect of DTNB on the pheromone response of the recipient cell was specific to an initial stage of the differentiation; once it had initiated, the reagent had no effect on its progression. The results suggested that dithiothreitol enhances and DTNB impairs the efficiency with which the pheromone triggers sexual d differentiation. The reaction of DTNB with cellular protein sulfhydryls was highly restricted to those at the exterior surface of the membrane due to the impermeability of the reagent through the membrane. Phosphorylation of endogenous proteins, which is modulated by the pheromone added to an in vitro phosphorylation system, was also blocked by DTNB. The results showed that sulfhydryl groups are involved in the pheromone hydrolysis by the surface endopeptidase of the recipient cell and that pheromone metabolism is indispensable for the signaling reaction. We suggest that the modulation of protein phosphorylation of membrane proteins by the pheromone is an initial transmembrane response coupled to pheromone metabolism.

Animals↗
PubMed1990

Giant axonal neuropathy: studies with sulfhydryl donor compounds.

Giant axonal neuropathy (GAN) is a disorder characterized pathologically by distal neurofilament-filled bulbous swellings in axons, and widespread collection of intermediate filaments, including masses of vimentin filaments in cultured skin fibroblasts. A morphologically similar neurofibrillary disorder is produced by acrylamide and the toxic hexacarbons, agents which bind to thiol groups. We report, in GAN fibroblasts, inhibition of vimentin filament aggregation by dithiothreitol and penicillamine, sulfhydryl donor compounds which stabilize thiols. In addition, we describe clinical improvement in a GAN patient treated with penicillamine, despite earlier progressive disease. These findings support the hypothesis of disordered thiol metabolism in GAN, and open up avenues for further research.

Adolescent↗
PubMed1968

Active sugar transport by the small intestine. The effects of sugars, amino acids, hexosamines, sulfhydryl-reacting compounds, and cations on the preferential binding of D-glucose to tris-disrupted brush borders.

Tris-disrupted and intact brush border membrane preparations from mucosa of hamster jejunum were capable of preferentially binding actively transported D-glucose in a similar manner. Density gradient centrifugation of the Tris-disrupted brush borders indicated that D-glucose was bound to a fraction containing the cores or inner material of the microvilli. The properties of this binding were examined with the Tris-disrupted brush border preparation. Actively transported sugars competitively inhibited preferential D-glucose binding, whereas no effect was observed with nonactively transported sugars. Neither actively nor nonactively transported amino acids affected D-glucose binding. D-Glucosamine, which is not actively transported, was inhibitory to preferential D-glucose binding as well as to the active transport of D-glucose by everted sacs of hamster jejunum. No inhibitory effect was observed with the same concentration of D-galactosamine. Preferential D-glucose binding was also inhibited by sulfhydryl-reacting compounds, Ca(2+), and Li(+) ions. On the other hand, Mg(2+) was shown to be stimulatory and Na(+), NH(4) (+), and K(+) had no effect on this phenomenon. The results of these experiments suggest that preferential D-glucose binding to brush borders is related to the initial step in active sugar transport by the small intestine.

Amino Acids↗
PubMed1985

Role of sulfhydryls in the hepatotoxicity of organic and metallic compounds.

Endogenous sulfhydryl compounds serve a critical role in maintaining the function and viability of living systems. Glutathione (GSH) is the most abundant of these nonprotein thiols. During the past decade it has been demonstrated that sulfhydryls such as GSH also serve an important role in protecting vital nucleophilic sites in the liver from electrophilic attack by numerous classes of reactive chemicals. Organocompounds such as bromobenzene and acetaminophen which undergo microsomal metabolism yield reactive intermediates that are specifically inactivated by conjugation with sulfhydryls in the form of GSH. Thus, for organocompounds GSH is extremely important in protecting against toxic insults. More recently, other sulfhydryl compounds also have been found to serve a specific but as yet less defined role in protecting biological systems against chemically induced injury. Metals such as cadmium have a high affinity for sulfhydryls and the metal binding protein metallothionein binds cadmium with high affinity. The highly specific association of the metal with this sulfhydryl-enriched protein serves to effectively sequester the reactive cadmium ion. The central role of sulfhydryl equivalents in the detoxication of organo- and metallocompounds is similar; however, the mechanism by which this is achieved is fundamentally different.

Acetaminophen↗
PubMed1988

The reaction of sulfhydryl groups with carbonyl compounds.

The sulfhydryl groups of L-cysteine and reduced glutathione (GSH) react nonenzymatically with formaldehyde (F), acrolein (Al), acetaldehyde (AA), malondialdehyde (DAM), pyruvate (P), oxoglutarate (oxo-G) and glucose (G) to form thiazolidine derivatives. These reactions show different velocities and the adducts formed show different stabilities. The equilibrium constants K, as well as the rate constants kr for the reverse reaction, show considerable variation. The carbonyls reveal higher reactivity with sulfhydryl group of L-Cys than with those of GSH, and the stability of the adducts is higher than that of GSH. Al, F and AA react more rapidly with both thiol compounds than the other carbonyls, but the adducts are less stable. The sulfhydryl groups level of bovine serum albumin as well as those of high- and low-molecular thiols of human plasma is reduced in the presence of Al, F or DAM.

Chemical Phenomena↗