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PubMed1978

[Pharmacological effect of pentacyanonitrosylferrate and similar complex compounds].

Comparative studies were performed on the spasmolytic and hypotensive effects of pentacyanoferrates with different ligands (NO, NO2, NOS, NH3, H2O) and of hexacyanoferrates and other nitrosyl compounds. Besides sodium nitroprusside, the nitro and thionitro complexes in equimolar doses were found to cause hypotension and relaxation of the aortic strip of rabbits contracted by adrenaline and spasmolytic effects on the contracted guinea pig ileum. The liberated nitrosyl cation or its secondary product, nitrous acid, is thought to be responsible for the pharmacodynamic effects of these complex compounds. This is in agreement with the fact that also other nitrosyl compounds (nitrosyl perchlorate, nitrosyl-bis(dimethylglyoximato)cobaltIII) and free undissociated nitrous acid produce transient spasmolytic effects. Pentacyanoaquoferrate and hexacyanoferrateIII exert, presumably because of the oxydation of sulfhydryl groups, spasmolytic effects in vitro. Accordingly, their effects are prevented in the presence of sulfhydryl compounds such as glutathion or dithioerythrit.

Animals↗
PubMed1995

Sulfhydryl blocker-induced rat colonic inflammation is ameliorated by inhibition of nitric oxide synthase.

BACKGROUND & AIMS: Sulfhydryl compounds are essential in maintaining mucosal integrity, and nitric oxide may contribute to tissue injury. The aim of this study was to characterize experimental colitis induced by a sulfhydryl blocker. METHODS: Colitis was induced in rats by intracolonic administration of 0.1 mL 3% iodoacetamide with and without addition of 0.1 mg/mL NG-nitro-L-arginine methyl ester (L-NAME) to the drinking water. After death, the distal colonic segment was resected and weighed, and mucosal inflammatory mediator, myeloperoxidase, and NO synthase activities were determined. RESULTS: Iodoacetamide induced multifocal mucosal erosions and ulceration that were present for up to 1 week. At 3 weeks, the mucosa was almost intact. Colonic wet weight was maximal at 7 days. Myeloperoxidase activity and NO generation were increased in the first 72 hours, and NO synthase activity and prostaglandin E2 generation were increased up to 21 days. Leukotriene B4 and leukotriene C4 generation were increased up to 14 days. One week after iodoacetamide plus L-NAME treatment, lesion area was reduced by 85% and NO synthase activity by 52%. CONCLUSIONS: Inflammatory mediators have an important contribution to the pathogenesis of colonic injury induced by a sulfhydryl alkylator. The protective effect of L-NAME indicates that NO contributes to tissue injury and that its modulation may be a novel approach to treat inflammatory bowel disease.

Amino Acid Oxidoreductases↗
PubMed2002

The study on organic nitrates, part V. New derivatives of piperazine potential NO donors.

We have obtained a series of non-symmetrical 1,4-disubstituted derivatives of piperazine, with the structure of organic nitrates, as potential NO donors. These compounds were obtained from respective hydroxyl derivatives of piperazine in an esterification reaction by fuming nitric acid. The obtained nitrates were tested in-vitro by reaction with a sulfhydryl compound. The structure of the most active nitrate and its hydroxyl analogue was used for the calculation of geometrical optimization with the determination of 3D-QSAR by a semi-empirical method PM3 using HyperChem 4.5.

Esterification↗
PubMed1977

Intracellular reduction of the cupric ion of bleomycin copper complex and transfer of the cuprous ion to a cellular protein.

The cupric ion of the bleomycin copper complex has been shown to be reduced and transferred to a cellular protein by the following mechanism: Bleomycin approximately Cu2+ leads to Bleomycin plus Cu+ X Cu+ plus M leads to M approximately Cu+. The intracellular reducing agents (X) are suggested to be sulfhydryl compounds, because their action is inhibited by N-ethylmaleimide. The active group of the cellular protein (M) that binds with the cuprous ion is suggested to be a sulfhydryl group. The action of the bleomycin copper complex in causing DNA fragmentation in cells can be explained by the mechanism presented in this paper. This mechanism in cells is also supported by the temperature dependency of the action of the bleomycin copper complex on cells.

Animals↗
PubMed2000

Assay of zofenopril and its active metabolite zofenoprilat by liquid chromatography coupled with tandem mass spectrometry.

Zofenopril is a pro-drug designed to undergo metabolic hydrolysis yielding the active free sulfhydryl compound zofenoprilat, which is an angiotensin converting enzyme (ACE) inhibitor, endowed also with a marked cardioprotective activity. A simple, highly sensitive specific LC-MS-MS method was developed for the determination of zofenopril and zofenoprilat in human plasma. In order to prevent oxidative degradation of zofenoprilat and its internal standard, their free sulfhydryl groups were protected by treatment with N-ethylmaleimide (NEM), which produced the succinimide derivatives. The compounds and their corresponding fluorine derivatives, used as internal standards, were extracted from plasma with toluene. The reconstituted dried extracts were chromatographed and then monitored by a triple-stage-quadrupole instrument operating in the negative ion spray ionization mode. The method was validated over the concentration range of 1-300 ng/ml for zofenopril and 2-600 ng/ml for zofenoprilat. Inter- and intra-assay precision and accuracy of both zofenopril and zofenoprilat were better than 10%. The limit of quantitation was 1 ng/ml with zofenopril and 2 ng/ml with zofenoprilat. Extraction recovery proved to be on average 84.8% with zofenopril and 70.1% with zofenoprilat. Similar recoveries were shown by the above two internal standards. The method was applied to measure plasma concentrations of zofenopril and zofenoprilat in 18 healthy volunteers treated orally with zofenopril calcium salt at the dose of 60 mg.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2004

Chemical basis for the biological activity of imexon and related cyanoaziridines.

Chemical aspects of mode of action of imexon and related cyanoaziridines were studied. These compounds do not alkylate DNA nor react with the epsilon-amino groups of l-lysine, despite the presence of an aziridine ring. They do react readily with biologically important sulfhydryl compounds to give products derived from either aziridine ring opening, interaction with the cyano group of cyanoaziridines, or opening of the iminopyrrolidone ring of imexon. The products from reactions of imexon and related cyanoaziridines with thiols are not as potent as their parent compounds against tumor cells. These results are consistent with biological studies that show that the mechanism of cytotoxicity involves thiol depletion followed by oxidative stress leading to apoptosis.

Acetylcysteine↗
PubMed1983

Metabolism of caffeine by mouse liver microsomes: GSH or cytosol causes a shift in products from 1,3,7-trimethylurate to a substituted diaminouracil.

Incubation of [14C]caffeine with hepatic microsomes from male AKR/J mice resulted in the formation of several metabolites including 1,3,7-trimethylurate and 6-amino-5-(N-formylmethyl-amino)-1,3-dimethyluracil. These two compounds comprised about 60% of products and are major urinary metabolites in several animals. When cytosol was included during incubation, there was a 14-fold increase in yield of the uracil at the expense of the urate; the combination of the two metabolites remained about 60% of total products. Cytosol alone was catalytically inert. Glutathione and other sulfhydryl compounds reproduced the effect of cytosol, and the action of cytosol was accounted for quantitatively by its sulfhydryl content. We propose that an oxidized intermediate of caffeine en route to trimethylurate is reduced by glutathione to the ring-opened uracil derivative.

Animals↗
PubMed1987

Changes in the glutathione content of rat 9L cells induced by treatment with the ornithine decarboxylase inhibitor alpha-difluoromethylornithine.

Treatment of 9L cells with the ornithine decarboxylase inhibitor alpha-difluoromethylornithine (DFMO) depletes cells of putrescine and spermidine and sensitizes cells to the cytotoxic effects of the alkylating agent 1,3-bis(2-chloroethyl)-1-nitrosourea. Because depletion of intracellular levels of the sulfhydryl compound glutathione also increases the cytotoxicity of alkylating agents, the effect of DFMO on intracellular glutathione content was investigated to determine whether DFMO-induced sensitization could be explained by a sulfhydryl-related mechanism. Treatment of 9L cells with 1 mM DFMO caused no change in the glutathione concentration within 48 h; sensitization of cells to 1,3-bis(2-chloroethyl)-1-nitrosourea is generally studied after 48 h of treatment with DFMO. Incubation of cells with DFMO for longer periods caused an increase in glutathione that is related to the depletion of polyamines and not to a decrease in growth rate or a cell cycle effect. Increased glutathione content is not due to a decrease in glutathione catabolism, but rather to an apparent increase in the rate of synthesis of the tripeptide.

Alkylating Agents↗
PubMed1982

Effect of morphinone on opiate receptor binding and morphine-elicited analgesia.

Specific binding of 3H-naloxone to opiate receptors was found to be irreversibly inactivated by morphine. This inactivation exhibited pseudo-first-order kinetics. The presence of sulfhydryl compounds or morphine during incubation with morphinone proved good protection. Morphinone-pretreated mice blocked the analgesic effect of morphine. The possible mechanism for these observations is proposed as follows: morphinone binds covalently to sulfhydryl group of opiate receptors, and inactivates irreversibly opiate binding sites, thus blocking the analgesic effect of morphine.

Analgesia↗
PubMed1982

Kinetics of hypothiocyanite production during peroxidase-catalyzed oxidation of thiocyanate.

We report here a kinetic study of the generation of hypothiocyanite (OSCN-), a product of lactoperoxidase-catalyzed oxidation of thiocyanate ion. Previous studies have measured OSCN- by reactions involving the oxidation of sulfhydryl compounds. Our results show that a more suitable kinetic analysis of OSCN- can be based on absorbance changes measured at 235 nm. About 90% of the oxidation products of SCN- observed at 235 nm were reactive with sulfhydryls and could be reduced with 2-mercaptoethanol. Both thiocyanate and peroxide were rate-limiting and the formation of OSCN- was proportional to the initial concentration of H2O2 until an equimolar concentration of H2O2 and SCN- was reached. This equimolar concentration gave the maximum generation of OSCN-. High concentrations (greater than 100 micrograms/ml) of lactoperoxidase decreased OSCN- generation, but only if the SCN- was added to the enzyme prior to addition of H2O2. With lactoperoxidase concentrations exceeding 1 microgram/ml, the reaction velocity was rapid, but the decay of OSCN- was slow. Free H2O2 in the reaction mixture always resulted in rapid decay of OSCN-. Addition of varying concentrations of peroxide to solutions containing 1 microgram/ml of enzyme and [SCN-] = 5 mM gave a family of hyperbolic A235 vs. time curves. Both the initial slopes and the plateaus of these curves increased linearly with increasing initial peroxide concentrations up to [H2O2] = 0.4 mM, remained relatively constant in the range [H2O2] = 0.4 to 0.8 mM, and decreased rapidly above [H2O2] = 0.8 mM. These results are consistent with the following kinetic model: Hydrogen peroxide reacts rapidly with lactoperoxidase to produce compound I. This compound I oxidizes SCN- to OSCN- and also oxidizes OSCN- to O2SCN-. The OSCN- also reacts with SCN-. The formation of OSCN- is associated with the appearance of an absorbance peak at 225-235 nm. The oxidation of OSCN- by excess peroxide or its decomposition at high concentrations is associated with a decrease in A235 and the appearance of a peak at 245-255 nm. The extinction coefficient for OSCN- was determined to be 1.29 x 10(3) M-1 . cm-1. The second-order rate constant for the oxidation of thiocyanate by compound I was estimated to be 2 x 10(5) M-1 . s-1.

Kinetics↗
PubMed1982

Newly synthesized hypoxia-mediated drugs as radiosensitizers and cytotoxic agents.

Chinese hamster cells in culture were used to compare the radiosensitizing efficiency and cytotoxicity of misonidazole with several 2, 4 and 5 substituted nitroimidazoles. The two substituted compounds (SR 2508 and SR 2555) are similar to misonidazole in radiosensitizing effectiveness, but are significantly less toxic to hypoxic cells. This reduced cytotoxicity may result from either slower drug penetration or slower removal of non-protein sulfhydryl compounds (NPSH). The compound MJL-1-191-VII (a 4-nitroimidazole) is a much more effective radiosensitizer than would be predicted from its electron affinity. It appears to sensitize by two mechanisms, the first resulting from its electron affinity and the second as consequence of its rapid removal of endogeneous cellular NPSH; which are naturally occurring radioprotective substances.

Animals↗
PubMed1983

Metabolism of alanylalanyl-S-[N-(2-thioethyl)]aminopyridine-2, 6-dicarboxylic acid]cysteine by suspensions of Escherichia coli.

The attachment of 4-[N-2-(mercaptoethyl)]aminopyridine-2,6-dicarboxylic acid (MEPDA) to AlaAlaCys through a disulfide bond to the cysteine residue has been described (Boehm, J. C., Kingsbury, W. D., Perry, D., and Gilvarg, C. (1983) J. Biol. Chem. 258, 14850-14855). The peptide disulfide showed enhanced growth inhibitory properties in Escherichia coli compared to the free sulfhydryl compound. Genetic evidence was presented to show that this side chain-modified peptide utilizes the oligopeptide transport system to gain entry to the cell. Following transport of the peptide, MEPDA is liberated by disulfide exchange reactions with sulfhydryl-containing components of the cell pool. In this paper, we examine in more detail the metabolism of this peptide. Using gel filtration chromatography to examine filtrates from cell suspensions incubated with the peptide, it was shown that loss of the peptide from the medium is accompanied by a corresponding increase in a component having the properties of MEPDA. The release of sulfhydryl groups from the peptide by cell suspensions could be monitored by Ellman's reagent and was found to be dependent upon peptide transport. Following cleavage of the disulfide bond, MEPDA is able to cross the cytoplasmic membrane and exit from the cell as a relatively lipophilic uncharged metal chelate.

Biological Transport, Active↗
PubMed1991

Inhibition of rat brain prostaglandin D synthase by inorganic selenocompounds.

Various inorganic selenocompounds dose-dependently inhibited the rat brain prostaglandin (PG) D synthase, both in the purified enzyme preparation and in the crude brain supernatant. All of the quadrivalent selenium compounds tested had a very limited range of IC50 values in the purified enzyme (11-12 microM) and in the brain supernatant (9-15 microM). A divalent selenium compound was also inhibitory, but a hexavalent selenium compound was ineffective. In contrast, organic selenocompounds such as selenomethionine and selenourea had no effect on the PGD synthase activity. Furthermore, sodium sulfate and sodium sulfite up to 10 mM did not inhibit the activity. The inhibition by selenium required the preincubation of the metal with sulfhydryl compounds such as dithiothreitol (DTT), indicating that the formation of selenotrisulfide or some other adduct(s) is essential for the inhibition. Furthermore, the inhibition was reversed by an excess amount of dithiothreitol, suggesting that the selenotrisulfide derivative of DTT binds to the SH group of the PGD synthase. The kinetic analysis revealed the inhibition by selenite to be noncompetitive with a Ki value of 10.1 microM. On the other hand, glutathione-dependent PGD synthase from rat spleen was much less inhibited, and PGF synthase and PGD2 11-ketoreductase activities were not inhibited by the selenium compound.

Animals↗
PubMed1995

Nitric oxide-induced nitration of catecholamine neurotransmitters: a key to neuronal degeneration?

Exposure of the neurotransmitters dopamine (1a) and norepinephrine (1b), as well as of other catechol compounds (1c-e), to nitric oxide (NO) in aerated phosphate buffer at room temperature leads to the corresponding 6-nitroderivatives (2a-e) in yields higher than 80%. Formation of nitration products depends on the presence of oxygen and is inhibited by excess ascorbic acid, whereas sulfhydryl compounds, e.g. cysteine, and scavengers of reactive oxygen species, such as catalase and superoxide dismutase, exert no significant inhibitory effect. O-Methylated catechols are poorly or not reactive toward NO. These and other observations are consistent with a mechanism involving coupling of a semiquinone radical with NO or a higher oxide, e.g. nitrogen dioxide (NO2). The observed formation of potentially toxic 6-nitrocatecholamines under physiologically relevant conditions may open new perspectives to an understanding of the biochemical processes underlying NO-induced toxicity and neuronal degeneration.

Ascorbic Acid↗
PubMedDate not supplied

Induction of sister-chromatid exchanges by N-nitrosocimetidine in cultured human lymphocytes and its inhibition by chemical compounds.

The effect of nitrosocimetidine (NC) on the frequency of sister-chromatid exchanges (SCEs) in human lymphocytes has been studied. The frequency of SCEs induced by a 1-h exposure to 2.6 X 10(-4) M NC was 4-fold greater than that in the solvent control. A 72-h exposure to NC had a similar dose-related effect. We also examined the effect of the sulfhydryl compounds cysteine, cysteamine, cystamine and glutathione, the reducing agent dithionite, and vitamins C and E on the NC-induced SCEs. None of these compounds induced SCEs. Cysteine, cysteamine, and cystamine significantly reduced the number of NC-induced SCEs, and the others did not.

Ascorbic Acid↗
PubMed1975

Expression in organ culture of agouti locus genes of the mouse.

CLEFFMANN (1963) reported that pigment cells of the lethal yellow (A-y/a) genotype change to black immediately upon cultivation, and continue to produce black pigment unless sulfhydryl reagents are added to the culture medium. We have attempted to repeat this observation and have not been able to do so. We also have been unable to indue the synthesis of yellow pigment by adding glutathione to cultures of agouti (A/A) skin. We therefore suggest that hypotheses which attempt to explain the action of agouti locus genes on the basis of effects of sulfhydryl compounds be considered with caution.

Animals↗