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PubMed1986

Possible regulation mechanism of microsomal glutathione S-transferase activity in rat liver.

After rats were injected with the reduced glutathione (GSH) depletor phorone (diisopropylidene acetone, 250 mg/kg, i.p.), there was a significant increase in microsomal glutathione S-transferase activity in the liver. The maximum activity was observed 24 hr after injection and was about 2-fold that of the control activity. Diethylmaleate (500 mg/kg, i.p.) had the same effect. Twenty-four hours after phorone injection (250 mg/kg, i.p.), the concentrations of GSH and oxidized glutathione (GSSG) in the liver were increased about 2-fold. Under the same conditions, the level of mixed disulfides with microsomal proteins (GSS-protein) was also increased. Further, the activity of microsomal glutathione S-transferases was increased by the in vitro addition of disulfide compounds such as GSSG, cystine and homocystine, and the activity increased by GSSG was reduced to control levels by incubating with the corresponding sulfhydryl compounds such as GSH, cysteine and homocysteine respectively. Thus, microsomal glutathione S-transferase activity appears to be regulated by the formation and/or cleavage of a mixed disulfide bond between the sulfhydryl group present in the enzyme and GSSG. Therefore, the increase of microsomal glutathione S-transferase activity after phorone injection may be due to the formation of a mixed disulfide bond between the sulfhydryl group in the enzyme and GSSG.

Animals↗
PubMed2003

Protective effects of steroid saponins from Paris polyphylla var. yunnanensis on ethanol- or indomethacin-induced gastric mucosal lesions in rats: structural requirement for activity and mode of action.

The methanolic extract from the rhizomes of Paris polyphylla SM. var. yunnanensis (FR.) H-M. was found to potently inhibit ethanol-induced gastric lesions in rats. Through bioassay-guided separation, four known spirostanol-type steroid saponins, pennogenin 3-O-alpha-L-rhamnopyranosyl(1-->2)-[alpha-L-arabinofuranosyl(1-->4)]-beta-D-glucopyranoside (1), pennogenin 3-O-alpha-L-rhamnopyranosyl(1-->4)-alpha-L-rhamnopyranosyl(1-->4)-[alpha-L-rhamnopyranosyl(1-->2)]-beta-D-glucopyranoside (2), diosgenin 3-O-alpha-L-rhamnopyranosyl(1-->2)-[alpha-L-arabinofuranosyl(1-->4)]-beta-D-glucopyranoside (3), and diosgenin 3-O-alpha-L-rhamnopyranosyl(1-->4)-alpha-L-rhamnopyranosyl(1-->4)-[alpha-L-rhamnopyranosyl(1-->2)]-beta-D-glucopyranoside (4), and a new furostanol-type steroid saponin, parisaponin I (5), together with two known furostanol-type steroid saponins, trigofoenoside A (6) and protogracillin (7), were isolated from the active fraction. Compounds 1-4 (1.25-10 mg/kg, po) strongly inhibited gastric lesions induced by ethanol and indomethacin. With regard to structural requirement of steroid saponins, the 3-O-glycoside moiety and spirostanol structure were found to be essential for the activity and the 17-hydroxyl group in the aglycon part enhanced the protective effects against ethanol-induced gastric lesions. The protective effects of 1 and 3 against ethanol-induced gastric lesions were attenuated by pretreatment with indomethacin and N-ethylmaleimide. Compounds 1 and 3 weakly inhibited acid secretions in pylorus-ligated rats. These findings suggested that endogenous prostaglandins and sulfhydryl compounds were involved in the protective activity.

Animals↗
PubMed1973

Multiple forms of acidic endopeptidase from germinated barley.

An endopeptidase preparation from germinated barley Hordeum vulgare L., cv. Trophy, purified by affinity chromatography and density-gradient electrofocusing, consisted of three or four components. The preparation was only partly resolved by electrofocusing, with evidence of three possible components (pI 4.15, 4.28, and 4.37). Gel filtration on Sephadex G-75 yielded an asymmetrical peak, the major part of which corresponded to a molecular weight of 14,100, with evidence of one larger and two smaller components. The activity of the preparation was sulfhydryl-dependent; cysteine was the most effective of several sulfhydryl compounds tested. The preparation was sensitive to O(2) in the absence of metal chelating agents and was inhibited by sulfhydryl reagents. It showed very narrow concentration tolerances for both cysteine and a substrate, N,N-dimethylhemoglobin. The Km value on N,N-dimethylhemoglobin at pH 3.8 was 0.064 to 0.067% (w/v) substrate; V(max) was 0.80 to 0.83 A(340) per hour. Normal enzyme activity and molecular-size distribution were observed when the endopeptidases were extracted in the inhibited state and subsequently reactivated, thus ruling out the possibility that the enzymes might be autolytic artifacts that arose during extraction and purification.

Journal Article↗
PubMed1984

Enhancing activity of rat tissue extracts for induction of lambda prophage by L-azaserine.

We studied the effect of rat tissue extracts on induction of lambda prophage in Escherichia coli (lambda) by L-azaserine. Hepatic and pancreatic extracts, primarily the cytosolic fraction, markedly increased the rate of induction. Hepatic extracts from lipotrope-deficient rats were somewhat more active than extracts from normal rats. The enhancing activity in normal rat hepatic cytosol was partially characterized. It reduced by about one-half the dose of azaserine required for a given purpose. The enhancement was increased by preincubating the bacterial cells with cytosol; cells retained the effect after cytosol was removed. Enhancing activity was inhibited strongly by the amino acids phenylalanine, tryptophan, and tyrosine; to lesser extents by leucine, methionine, and serine; and not at all by proline or glutamine. It was eliminated by dialysis of the cytosol and reduced by omission of nicotinamide adenine dinucleotide phosphate (NADP) from the reaction mixture. Heating the cytosol to 60 degrees C or 80 degrees C or varying the pH of the reaction mixture from 6 to 8 had no significant effect. Treating the cytosol with trypsin appeared to release an inhibitor of the activity. Glutathione, cysteine, and beta-mercaptoethanol also enhanced lambda induction by azaserine, but the cytosolic activity was not affected by the thiol-inactivating compound diethylmaleate (DEM). The results suggest that factors in cytosol interact with bacterial cells to facilitate transport of azaserine into the cells, primarily through the aromatic amino acid transport system. A small molecule, not a free thiol compound, appears to be involved. It may serve to establish reducing conditions protective for azaserine, the probable mechanism of action of sulfhydryl compounds.

Animals↗
PubMed1997

Hydrazide-containing inhibitors of HIV-1 integrase.

Inhibitors of HIV integrase are currently being sought as potential new therapeutics for the treatment of AIDS. A large number of inhibitors discovered to date contain the o-bis-hydroxy catechol structure. In an effort to discover structural leads for the development of new HIV integrase inhibitors which do not rely on this potentially cytotoxic catechol substructure, NSC 310217 was identified using a three-point pharmacophore search based on its assigned structure N-(2-hydroxybenzoyl)-N-(2-hydroxy-3-phenoxypropyl)hydrazine (1). When a sample of NSC 310217 was obtained from the NCI repository, it was shown to exhibit potent inhibition of HIV-1 integrase (3'-processing IC50 = 0.6 microgram/mL). In work reported herein, we demonstrate that NSC 310217, rather than containing 1, which has no inhibitory potency against HIV-1 integrase, is comprised of roughly a 1:1 mixture of N-(2-hydroxybenzoyl)-N'-(2-hydroxy-3-phenoxypropyl)hydrazine (6) and N,N'-bis-salicylhydrazine 7, with all inhibitory potency residing with compound 7(IC50 = 0.7 microM for strand transfer). In subsequent structure-activity studies on 7, it is shown that removing a single amide carbonyl (compound 14, IC50 = 5.2 microM) or replacing one aromatic ring system with a naphthyl ring (compound 19, IC50 = 1.1 microM) can be accomplished with little loss of inhibitory potency. Additionally, replacing a single hydroxyl with a sulfhydryl (compound 23, IC50 = 5.8 microM) results in only moderate loss of potency. All other modifications examined, including the replacement of a single hydroxyl with an amino group (compound 22), resulted in complete loss of potency. Being potent, structurally simple, and non-catechol-containing, compounds such as 7 and 14 may provide useful leads for the development of a new class of HIV integrase inhibitor.

Databases, Factual↗
PubMed1994

Mechanism of the inhibition of hog gastric H+,K(+)-ATPase by the seleno-organic compound ebselen.

The effect of 2-phenyl-1,2-benzisoselenazol-3 (2H)-one (ebselen, CAS 60940-34-3), a seleno-organic compound, on the partial reaction steps of H+,K(+)-ATPase in hog leaky gastric vesicles was examined. Ebselen inhibited K(+)-dependent ATPase activity (IC50 = 0.06 mumol/l), phosphoenzyme formation (IC50 = 0.25 mumol/l), and K(+)-dependent p-nitrophenylphosphatase activity (IC50 = 0.09 mumol/l: dephosphorylation step of this enzyme). Furthermore, this compound prevented changes in the fluorescence intensity of flourescein isothiocyanate-labeled enzyme (E1-->E2K form, IC50 = 0.33 mumol/l). Pretreatment with 2 mmol/l of dithiothreitol (DTT) used as a sulfhydryl compound completely protected against these inhibitory effects. These findings indicate that ebselen-induced inactivation of gastric H+,K(+)-ATPase may result from prevention of the partial reaction steps, which include phosphorylation, dephosphorylation and conformational change (E1-->E2K form), through interference with sulfhydryl groups of the enzyme.

4-Nitrophenylphosphatase↗
PubMed1999

Myeloperoxidase-catalyzed oxidation of tyrosine.

The oxidation of tyr by myleoperoxidase (MPO) is postulated to play a role in atherosclerotic plaque formation. MPO has been localized in plaques and a product of MPO-catalyzed oxidation of tyr, dityrosine, also found in plaques, is proposed to be a protein cross-linking agent. We have performed kinetic studies on the oxidation of tyr by MPO and investigated the role of substrate size on its oxidation. The kinetics of MPO-catalyzed oxidation of tyr where the tyr is free tyr, the dipeptides, tripeptides, and polypeptides were studied by stopped-flow methods. The rate of reaction with enzyme intermediates compound I and compound II are decreased with increasing substrate size. The amount of dityrosine formed was also decreased with increasing substrate size. The ability of sulfhydryl compounds to inhibit MPO-dependent dityrosine formation was investigated with reduced glutathione, cys, and met. Glutathione and cys both served as substrates for MPO compound I but not compound II, whereas met was not a substrate for either compound I or II. Met, an amino acid postulated to act as a "last chance" antioxidant for proteins, was not able to inhibit dityrosine formation from MPO-catalyzed oxidation of tyr. Glutathione and cys caused partial inhibition; however, it is possible that this inhibition was due to their ability to react directly with MPO rather than trapping the tyr radicals.

Animals↗
PubMed1990

New angiotensin converting enzyme inhibitors. Their role in the management of hypertension.

The introduction of orally active angiotensin converting enzyme (ACE) inhibitors has revolutionized the treatment of hypertensive disorders and provided an effective alternative for the management of congestive heart failure (CHF). By interfering with the formation of angiotensin II, the active agent of the renin system, ACE inhibitors block the system's vasoconstrictive and sodium-retaining effects, with a consequent reduction in systemic blood pressure. The net effect is improved blood flow and reduced cardiac work. Thus, ACE inhibitors are likely to improve cardiac work capacity and quality of life. Their mechanism of action differs markedly from that of traditional antihypertensive agents which lower blood pressure while reducing cardiac output and blood flow. Since the primary action of ACE inhibitors is to block the renin system, a dramatic response to monotherapy suggests a large renin factor while the lack of a response suggests a low-renin state more amenable to treatment with a diuretic or calcium antagonist. Because of their many attributes, ACE inhibitors are increasingly used as first-line therapy for the treatment of hypertension or CHF. The prototype orally active ACE inhibitor, captopril, is a sulfhydryl compound with a good safety profile at the recommended dosages but reported toxicity at higher dosages. Second-generation ACE inhibitors (eg, enalapril and quinapril) are more potent sulfhydryl-free esters with a greater affinity for the converting enzyme. These newer agents are pro-drugs requiring ester hydrolysis to form the active free acid compound.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin II↗
PubMedDate not supplied

[Chemiluminescence in a stimulated polymorphonuclear leukocytes--luminol system: suppression by thiols].

The effect of some scavengers of thiol nature, which eliminate all reactive oxygen species and oxidants with reactive chlorine, on the luminol-enhanced chemiluminescence of polymorphonuclear leukocytes was studied. The use of two scavengers of this type (penetrating and not penetrating into the cell) made it possible to separate the luminescence of cell structures from the luminescence generated by oxidants in the surrounding medium. It was found that about a half of luminol luminescence is due to its oxidation in the medium surrounding the cell, and it is completely inhibited by the nonpenetrating reduced glutathione. The cell itself is a source of a considerable portion of luminescence, and this luminescence is quenched by penetrating sulfhydryl compounds such as dithiothreitol and N-acethyl cysteine. Reduced glutathione, which penetrates into cells and whose action is due only to the sulfhydryl group, is recommended as a candidate for the selective neutralization of extracellular oxidants.

Acetylcysteine↗
PubMed1996

A computer program for quantification of SH groups generated after reduction of monoclonal antibodies.

Reduction of disulfide bonds to sulfhydryl (SH) groups for direct radiolabeling of antibodies for immunoscintigraphic studies of colorectal and other cancers continues to be of considerable research interest. We have developed a general strategy and a versatile computer program for the quantification of the number of SH per molecule of antibody (Ab) generated after the treatment of monoclonal antibodies (MAbs) with reducing agents such as 2-mercaptoethanol (2-ME), stannous chloride (SnCl2), dithiothreitol (DTT), dithioerythritol (DTE), ascorbic acid (AA), and the like. The program we describe here performs an unweighted least-squares regression analysis of the cysteine standard curve and interpolates the cysteine concentration of the samples. The number of SH groups per molecule of antibody in the 2-mercaptoethanol and in the other reducing agents was calculated from the cysteine standard curve using Ellman's reagent to develop the yellow color. The linear least-squares method fit the standard data with a high degree of accuracy and with the correlation coefficient r of 0.999. A program has been written for the IBM PC compatible computer utilizing a friendly menu to interact with the users. The package allows the user to change parameters of the assay, to calculate regression coefficients slope, intercept and its standard errors, to perform statistical analysis, together with detailed analysis of variance, and to produce an output of the results in a printed format.

Animals↗
PubMed1995

Effect of NDGA on beef heart mitochondria and EMT6 mouse mammary carcinoma cells.

The inhibition of mitochondrial succinate cytochrome c reductase by nordihydroguaiaretic acid (NDGA) was measured in vitro under aerobic and hypoxic conditions. The photodynamic effect of NDGA on EMT6 mouse mammary carcinoma cells was also investigated in vitro under aerobic and hypoxic conditions. NDGA strongly inhibited succinate cytochrome c reductase, which contains the mitochondrial electron transport Complexes II and III. By comparing the I50 values of aerobic and hypoxic assays, NDGA inhibition was found to be oxygen-independent. This finding suggests that oxygen is not involved in the inhibitory effect of mitochondrial respiration by NDGA. Similarly, our data demonstrate that NDGA-induced cytotoxicity towards EMT6 tumor cells is neither light-dependent nor oxygen-dependent. A dose-dependent loss of viability of EMT6 cell was observed although the toxicity of NDGA towards EMT6 cells was not strong, with an LC50 in the 200 microM range. NDGA caused a depletion of mitochondrial sulfhydryl groups. Sulfhydryl compounds, GSH and cysteine, prevented the inhibition of succinoxidase activity by NDGA. This suggests that NDGA exerts its biological effects by the depletion of sulfhydryl groups in key biochemical systems related to mitochondrial function.

Aerobiosis↗
PubMed1997

Induction of cystine transport and other stress proteins by disulfiram: effects on glutathione levels in cultured cells.

Disulfiram (Antabuse) (DSF) has been reported to protect rats and other animals from the effects of hyperbaric hyperoxia at 4 to 6 ATA (atmospheres). In contrast, DSF and diethyldithiocarbamate (DDC), its metabolite, accelerate the toxic effects in rats of 100% oxygen at 1 to 2 ATA. We have examined the effects of DSF and DDC on glutathione (GSH) levels in bovine pulmonary artery endothelial cells and Chinese hamster ovary cells. Increases in intracellular GSH occurred 8 to 24 h after addition of DSF to the culture media. These increases in intracellular GSH were associated with increases in the rate of uptake of cystine into the cells. DDC was a less effective inducer of cystine uptake and increased intracellular GSH levels than was DSF. At the concentrations used, neither DDC nor DSF caused significant decreases in intracellular superoxide dismutase levels. Exogenous sulfhydryl compounds including GSH and cysteine partially blocked the induction of cystine transport by DSF or DDC, suggesting that the induction might be mediated through a sulfhydryl reaction between DSF and some cellular components. The increases in GSH in the cultured cells were not significant by 4 h of exposure. In contrast, other stress proteins including heme oxygenase are induced by 2 to 4 h after DSF addition. In previously reported in vivo studies, DSF treatment protected against hyperbaric oxygen damage after as little as 1 to 4 h pre-exposure. This suggests that effects of DSF exposure other than GSH augmentation may be responsible for the protective effects seen in vivo.

Animals↗
PubMed1984

Effects of diethyldithiocarbamate, an inhibitor of interferon antiviral activity, upon human natural killer cells.

In support of a postulated role of the Cu++-dependent enzyme, superoxide dismutase (SOD), in antiviral effects of interferon (IFN), a close correspondence was previously shown to exist between inactivation of cellular SOD and concomitant blockade of IFN antiviral activity in fibroblasts by the Cu++-chelating agent, diethyldithiocarbamate (DDC). To further define the extent of "anti-IFN" activity, we initiated studies of DDC effects on IFN stimulation in the NK cell system. Unexpectedly, DDC directly inhibited cytotoxicity mediated by unstimulated NK cells. Pronounced inactivation occurred rapidly (less than 30 min), but was spontaneously reversible in the absence of DDC. Neither cell viability nor lymphocyte binding to target cells was detectably affected. Preincubation of DDC with Cu++ or Zn++ failed to neutralize its inhibitory effects nor could function be restored in DDC-pretreated NK cells by subsequent addition of Cu++, Zn++, Mg++, or Ca++. DDC treatment that inactivated NK cells did not detectably alter lymphocyte SOD activity. Thus, inhibition was probably not attributable to chelating properties of DDC. N-ethyl maleimide (NEM) and para-( hydroxymercuri ) benzoic acid ( PMBA ), enzyme inhibitors that preferentially react with sulfhydryl groups, both inactivated NK cells in a time- and dose-dependent manner similar to that of DDC. Preincubation with the sulfhydryl compound, cysteine, neutralized in parallel fashion the capacity of NEM, PMBA , and DDC to inhibit NK cell activity. Thus, a previously unreported reactivity of DDC with sulfhydryl groups appeared to be the basis of inhibition. NK cells incubated 1 hr with IFN and subsequently cultured 17 to 23 hr without IFN were activated to an extent comparable to cells continuously incubated 18 to 24 hr with IFN. Exposure to IFN for 1 hr was therefore sufficient to commit NK cells to acquisition of a fully activated state. Whether preactivated by a 1-hr or 18- to 24-hr IFN treatment, activated NK cells retained the DDC-sensitive phenotype characteristic of fresh unstimulated NK cells. Thus, prolonged IFN treatment did not render NK cells resistant to DDC or preferentially activate a DDC-sensitive NK cell subset. An 18- to 24-hr incubation of DDC-pretreated cells in the continual presence of IFN resulted in the boosting of NK cell activity. However, the 1-hr IFN pulse treatment protocol was consistently ineffective in boosting when IFN was added just after DDC-pretreatment. These results strongly suggested that DDC temporarily rendered NK cells unresponsive to what, under normal circumstances, approximated an optimally potentiating IFN stimulus.(ABSTRACT TRUNCATED AT 400 WORDS)

2',5'-Oligoadenylate Synthetase↗