[Methods for demonstration and determination of sulfhydryl compounds].
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Sulfhydryl Compounds↗
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Thermosensitization by sulfhydryl compounds of exponentially growing Chinese hamster cells.
The effect of various sulfhydryl compounds on the survival of exponentially growing monolayer cultures of Chinese hamster cells (HA1) heated to temperatures of 37-43 degrees was examined. Concentrations of cysteamine which were nontoxic or minimally toxic at room temperature or 37 degrees became increasingly toxic at elevated temperatures, greatly potentiating the killing produced by heat alone in the absence of cysteamine. This enhancement of hyperthermia-induced cell killing increased with increasing cysteamine concentration, increasing duration of cysteamine exposure, and increasing temperature. Studies with synchronized Chinese hamster cells heated at 43 degrees for 1 hr in the presence of 16 mM cysteamine demonstrated that the potentiation of heat killing occurred in all phases of the cell cycle. Similarly, enhancement of hyperthermia-induced cell killing was seen for asynchronous cells exposed to 2-amino-ethylisothiourium bromides and cysteine, but the magnitude of the effect differed for the various sulfhydryl compounds.
Animals↗
Evidence for the involvement of sulfhydryl compounds in the inhibition of cellular DNA synthesis by selenite.
Previous studies have demonstrated that selenite inhibits cellular DNA synthesis. We have now found that endogenous cellular sulfhydryl compounds are involved in this effect of selenite. Treatment of cells with diethylmaleate, which produces a nonspecific depletion of cellular sulfhydryl compounds, resulted in a significant decrease in the sensitivity of DNA synthesis to inhibition by selenite. This decrease was eliminated by exogenous cysteine, but not by cystine. Similarly, DNA synthesis in nuclei isolated from diethylmaleate-treated cells was much less sensitive to inhibition by selenite than was synthesis in nuclei isolated from control cells. In contrast, treatment with buthionine sulfoximine, which specifically depletes the cells of glutathione, had no effect on the inhibition of DNA synthesis by selenite, indicating that cellular glutathione is not involved in the inhibition. Nevertheless, glutathione is able to compensate to some extent for the decreased level of sulfhydryl compounds in nuclei isolated from DEM-treated cells (although not as well as cysteine). Thus, although glutathione is able to potentiate the inhibition of cellular DNA synthesis by selenite, it apparently does not function in this capacity in the cell.
Buthionine Sulfoximine↗
Rapid inactivation of 3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone (MX), a potent mutagen in chlorinated drinking water, by sulfhydryl compounds.
The mutagenic activity of 3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone (MX), which is formed during chlorination of drinking water, was effectively inhibited by sulfhydryl compounds such as cysteine, cysteamine, glutathione, dithiothreitol and 2-mercaptoethanol. Preincubation of 0.5 micrograms MX with 15 micrograms cysteine (molar ratio 1:37) in a phosphate buffer (pH 6.0-8.0) at 37 degrees C for 15 min prior to exposure of bacterial cells depleted the mutagenic activity of MX. Together with the result showing a change in the UV spectra, it is suggested that sulfhydryl compounds inactivate MX by direct chemical interaction before MX induces DNA damage. On the other hand, a variety of antioxidants other than the sulfhydryl compounds showed no inhibitory effects. Investigation using structural analogs of cysteine revealed that the thiol moiety was indispensable for antimutagenic activity and the amino moiety appeared to enhance the MX-inactivating reaction of the SH group.
Antimutagenic Agents↗
Involvement of endogenous nitric oxide and sulfhydryl compounds in ebrotidine-induced gastroprotection.
The role of endogenous nitric oxide and sulfhydryl compounds in the prevention by ebrotidine (N-[(E)- [[2-[[[2-[(diaminomethylene)amino]-4-thiazolyl]methyl]thio]ethyl]amino] methylene]-4-bromo-benzenesulfonamide, CAS 100981-43-9, FI-3542) (100 mg/kg i.g.) of ethanol-induced gastric damage in rats was demonstrated. When the animals were pretreated with N-nitro-L-arginine methyl ester, an inhibitor of nitric oxide synthase, at the dose of 10 mg/kg i.v., the mucosal lesions were aggravated and the gastroprotective action of ebrotidine decreased from 85% to 24%. This decrease in ebrotidine protection was antagonized by L-arginine (200 mg/kg i.v.), the lesion inhibition rate being 69%. D-arginine (200 mg/kg i.v.) was ineffective and the inhibition afforded by ebrotidine was only 14%. Pretreatment with N-ethylmaleimide, a sulfhydryl blocker, at the dose of 50 mg/kg s.c., increased the mucosal lesion induced by ethanol, and the gastroprotective action of ebrotidine decreased from 75% to 9%. These results suggest that endogenous nitric oxide and sulfhydryl compounds play a crucial role in the gastroprotective activity of ebrotidine.
Animals↗
Inhibition of RNA and DNA polymerases by the product of the reaction of selenite with sulfhydryl compounds.
Sodium selenite has previously been shown to inhibit DNA and RNA synthesis in both intact cells and isolated nuclei. Nevertheless, DNA and RNA polymerases, the enzymes responsible for this synthesis, are insensitive to inhibition by selenite. Several DNA and RNA polymerases have now been shown to be inhibited by selenite in the presence of sulfhydryl compounds. This inhibition is due to the reaction of selenite with the sulfhydryl compounds to form selenotrisulfide derivatives which inhibit the enzymes. The selenotrisulfides decrease the Vmax of the polymerase reaction and increase the apparent Km for the triphosphates, but do not alter the apparent Km of the enzyme for the DNA template. There are differences in potency between selenotrisulfides formed from similar sulfhydryl compounds such as mercaptoethanol and mercaptoethylamine. There are also differences in the sensitivity of different polymerases to inhibition by the selenotrisulfides.
Chemical Phenomena↗
Glutathione prevents ethanol induced gastric mucosal damage and depletion of sulfhydryl compounds in humans.
Whether parenteral administration of reduced glutathione prevented ethanol induced damage to and depletion of sulfhydryl compounds in the human gastric mucosa was investigated. Ten healthy volunteers underwent endoscopy on three separate occasions. Gastric mucosal damage was induced by spraying 80% ethanol on to the gastric mucosa through the biopsy channel of the endoscope. The gastric mucosal score, total sulfhydryls, glutathione, and cysteine were evaluated in basal conditions and after ethanol administration with and without pretreatment with parenteral glutathione. Glutathione significantly decreased the extent of ethanol induced macroscopic injury to the mucosa of the gastric body and antrum. Glutathione's protective effect is associated with appreciable inhibition of ethanol induced depletion of gastric sulfhydryl compounds. This is the first report of protection against ethanol induced gastric mucosal damage by a sulfhydryl containing agent in humans.
Adult↗
The reaction between organic nitrates and sulfhydryl compounds. A possible model system for the activation of organic nitrates.
The rate of loss of the sulfhydryl group, determined with the Ellman reagent, was used to derive second order rate constants for the reaction of a series of organic nitrates with a series of sulfhydryl compounds. For the organic nitrates, increases in the rate of reaction with cysteine, in general, ran parallel both with increases in pharmacological potency (flow in the Langendorff heart) and with increases in total clearance. Cysteine was the most active sulfhydryl compound examined, which is compatible with a possible role as an important nitrate receptor. Under some conditions the rate of loss of the sulfhydryl group was much greater than the rate of formation of nitrite ion. This indicates the presence of a reaction intermediate, probably a thionitrate. It is suggested that, in vivo, a thionitrate could function as an important intermediate in the activation of guanylate cyclase.
Animals↗
The changes in sulfhydryl compounds in plasma, liver and brain after acute and chronic ethanol administration in rats.
The content of sulfhydryl compounds in proteins and non-proteins of plasma, liver and brain after acute and chronic ethanol administration was investigated in rats. After ethanol ingestion for 4 weeks (6 g/kg, day 30% w/v) significant changes were observed in plasma proteins and in liver proteins and non-proteins. In brain proteins and non-proteins we did not find any changes in sulfhydryl compounds content after acute and chronic ethanol administration.
Alanine Transaminase↗
Sulfhydryl compounds inhibit the cyto- and geno-toxicity of o-phenylphenol metabolites in CHO-K1 cells.
The effects of cysteine and reduced glutathione (GSH) on the genotoxicity of o-phenylphenol (OPP) and its metabolites, phenylhydroquinone (PHQ) and phenylbenzoquinone (PBQ), were examined using the frequency of sister-chromatid exchanges (SCEs) and chromosome aberrations in CHO-K1 cells as parameters. Cytotoxic (cell-progression delay) and cytogenetic effects induced by a 3-h treatment with OPP, PHQ (100 micrograms/ml) or PBQ (50 micrograms/ml) with S9 mix after a 27-h expression time were inhibited by cysteine or GSH (3-10 mM). Materials corresponding to the cysteine or GSH adducts were found by HPLC in each incubation mixture. In the culture without S9 mix, PHQ and PBQ showed severe cytotoxicity since no metaphases could be obtained at doses over 25 and 5 micrograms/ml, respectively, and the sulfhydryl compounds inhibited the toxicity by the formation of adducts with PBQ and by inhibiting the formation of PBQ in the case of PHQ. With PHQ, the sulfhydryl compounds appeared to inhibit autooxidation. However, the sulfhydryl compounds did not inhibit the cytotoxic and cytogenetic effects caused by OPP in the cell mixture without S9 mix, but on the contrary intensified them. No adduct formation was detected in the incubation solution. On the basis of these results, it is considered that electrophilic quinone (PBQ) and/or semiquinone (phenylsemiquinone, PSQ) radicals, capable of binding to nucleophilic small molecules (such as cysteine and GSH) or (biological) macromolecules, are produced from metabolite PHQ in metabolic oxidation of OPP, and induce cyto- and geno-toxic effects in the cells. The cyto- and geno-toxic effects of OPP itself to the cells are clearly independent of any electrophilic radical reaction.
Animals↗
Protective effect of sulfhydryl compounds on acute toxicity of morphinone.
The ability of sulfhydryl compounds to provide protection against the acute toxicity of morphinone was investigated in mice. Subcutaneous administration of morphinone produced a reduction of hepatic non-protein sulfhydryl concentration. Pretreatments of mice with glutathione or cysteine significantly increased the survival rate of mice given a lethal dose of morphinone, whereas morphinone lethality was markedly potentiated by diethyl maleate. On the other hand, the administration of morphine produce a dose dependent reduction of hepatic non-protein sulfhydryl contents. However, neither glutathione nor cysteine protected mice from the acute toxicity of morphine. A possible explanation for these observations was proposed as follows: morphine is oxidized by morphine 6-dehydrogenase to morphinone, and the morphinone thus produced decreases the sulfhydryl contents in the liver. This mechanism is supported by the fact that morphinone reacts easily with glutathione and cysteine in vitro.
Animals↗
Sulfhydryl compounds may mediate gastric cytoprotection.
Ethanol induces hemorrhagic gastric erosions and causes a dose-dependent decrease in the concentration of nonprotein sulfhydryl compounds in rat gastric mucosa. Sulfhydryl-containing drugs protect rats from ethanol-induced gastric erosions, whereas sulfhydryl blocking agents counteract the mucosal cytoprotective effect of prostaglandin F2 beta. These observations suggest that endogenous nonprotein sulfhydryls may mediate prostaglandin-induced gastric cytoprotection and that sulfhydryl drugs may have potential for preventing or treating hemorrhagic gastric erosions.
Animals↗
The effect of sulfhydryl compounds on 5-fluorouracil toxicity and distribution.
The investigations performed revealed that sulfhydryl compounds (reduced glutathione, cysteine and mesna) reduced the acute and subacute toxicity of 5-fluorouracil in mice. The above compounds changed pharmacokinetics of 5-fluorouracil increasing its accumulation in tissue compartment. The studies on 5-Fu distribution revealed its increased concentration in certain organs after administration of only certain sulfhydryl-containing compounds and only after certain doses.
Animals↗
The role of sulfhydryl compounds in mammalian melanogenesis: the effect of cysteine and glutathione upon tyrosinase and the intermediates of the pathway.
The effect of cysteine and glutathione on mammalian melanogenesis has been studied. It has been shown that their action is mediated by two different mechanisms. (a) The reaction of the thiol groups with dopaquinone after the tyrosinase-catalyzed oxidation of tyrosine and dopa. This mechanism leads to the formation of sulfhydryl-dopa conjugates and finally sulfur-containing pigments, phaeomelanins instead of eumelanins. This fact might produce an inhibition of melanogenesis due to the slower rate of chemical reactions involved in the polymerization of such thiol-conjugates when compared to that of indoles. (b) The direct interaction between the sulfhydryl compounds and the tyrosinase active site. This interaction may regulate the activity of the enzyme. It is shown that Harding-Passey mouse melanoma tyrosinase is more sensitive to sulfhydryl compounds than mushroom tyrosinase. Cysteine always produces an inhibition of the tyrosinase hydroxylase and dopa oxidase activities of melanoma tyrosinase, this inhibition becoming greater as the cysteine concentration increases. On the other hand, glutathione produces an activation of the tyrosine hydroxylase activity below 3 mM and an inhibition at higher concentrations. The limit between the enzymatic activation and inhibition appears at glutathione concentrations similar to the physiological levels of this compound found in melanocytes. Although the switch from eumelanogenesis to phaeomelanogenesis occurs at much lower concentrations of glutathione, taking into account these data it is discussed that this sulfhydryl compound may regulate not only the type but also the amount of melanin formed inside melanocytes.
Animals↗
Effect of vitamins, antioxidants and sulfhydryl compounds on in vitro rat brain lipid peroxidation.
The effect of retinol, retinylacetate, alpha-tocopherol, alpha-tocopherylacetate, synthetic antioxidants (DPPD, BHT, DAH, and Ethoxyquine) sulfhydryl compounds (reduced glutathione and cysteine) on rat brain lipid peroxidation has been studied using the TBA method. Retinol and retinyl acetate inhibit brain lipid peroxidation, alpha-tocopherol is less effective than vitamin A, while alpha-tocopherol acetate has no antioxidant property. Ascorbic acid stimulates the peroxidation, at pH 5.0. The synthetic antioxidants are all potent inhibitors of brain lipid peroxidation, DPPD being the most effective, while the sulfhydryl compounds at a concentration of 1 x 10(-3)M has a slight potentiating effect.
Animals↗
Modification of ultraviolet radiation effects on the membrane of myelinated nerve fibers by sulfhydryl compounds.
The modification of the ultraviolet blocking of sodium channels and of the ultraviolet-induced potential shift of the gating parameters by means of the sulfhydryl compounds l-cysteine and 2-mercaptoethanol was investigated in the node of Ranvier under voltage-clamp conditions. The UV wavelength was 280 nm. The radiation-induced potential shift of the voltage-dependent gating parameters was prevented or even reversed by the action of the sulfhydryl compounds (internal application), while the blocking effect was not affected. It is concluded that the two radiation effects are caused by two separate photoreactions. Internally applied N-ethylmaleimide, binding specifically to protein-SH groups, exhibits an effect similar to the ultraviolet-induced potential shift, without affecting the maximum sodium permeability. Therefore, the ultraviolet-induced potential shift might be caused by a photocatalyzed oxidation of -SH groups of membrane proteins changing the surface charge density at the inner side of the nodal membrane.
Animals↗
Sulfhydryl compounds in melanocytes of yellow (Ay/a), nonagouti (a/a), and agouti (A/A) mice.
CLEFFMANN (1953, 1963a,b) has reported that yellow but not black melanocytes of agouti (A/A) rabbits contained reducing sulfhydryl compounds. We have attempted to repeat CLEFFMANN's observations in mouse melanocytes of the lethal yellow (Ay/a), nonagouti (a/a) and agouti (A/A) genotypes. Our results contradict those of CLEFFMANN and reveal that yellow and black melanocytes, regardless of genotype, possess equivalent amounts of histochemically detectable sulfhydryl compounds. These results do not support the hypothesis that agouti-locus genes act by controlling the sulfhydryl metabolism of pigment cells.
Animals↗
Nonprotein sulfhydryl compounds in canine gastric mucosa: effects of PGE2 and ethanol.
By use of an in vivo canine chambered stomach preparation in which the gastric mucosa was partitioned into two equal halves, the effect of topical 16,16-dimethyl PGE2 (DMPGE2) (1 microgram/ml of perfusate) and 8% and 40% ethanol on tissue levels of nonprotein sulfhydryl compounds was assessed. Both DMPGE2 and 8% ethanol significantly increased (P less than 0.005) mucosal levels of nonprotein sulfhydryls when compared with corresponding mucosa bathed with saline alone. In contrast, mucosa bathed with 40% ethanol showed significantly decreased levels. If mucosa was bathed with DMPGE2 or 8% ethanol prior to exposing the stomach to 40% ethanol, this depletion in sulfhydryl compounds was not observed. Since other experimental observations have shown that exogenously administered prostaglandins and mild irritants (such as low-dose alcohol) can prevent gastric mucosal damage by necrotizing agents (such as high-dose alcohol), our findings are consistent with the hypothesis that nonprotein sulfhydryls may play a role in mediating gastric mucosal protection.
16,16-Dimethylprostaglandin E2↗