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PubMed1989

Cysteamine and the endocrine pancreas: immunocytochemical, immunochemical, and functional aspects.

To evaluate the previously reported depletion of pancreatic somatostatin by cysteamine (beta-mercaptoethylamine), mice were injected subcutaneously with the drug at 300 mg/kg. Immunocytochemical analysis performed on sections from tissue taken at 4 h after the injection revealed an elimination of somatostatin-14-like immunoreactivity without alterations in the somatostatin-28(1-12)-like immunoreactivity. In sections from tissues taken at 24 h after injection, no differences between cysteamine-injected animals and controls were observed. Immunochemical analysis of somatostatin-14-like immunoreactivity in pancreatic extracts showed a significant reduction of the concentration (P less than 0.001). In contrast, no change in the insulin concentration was observed. Functionally, cysteamine lowered the plasma glucose levels at 1 h after injection; this effect persisted for 6 h. Plasma insulin levels were likewise reduced transiently by cysteamine. Concomitant administration of somatostatin did not influence these effects of cysteamine. The plasma glucose-lowering effect of cysteamine was seen also in alloxan-diabetic mice. We conclude that cysteamine alters the immunoreactive characteristics of pancreatic somatostatin without affecting the immunoreactivity of insulin, and that cysteamine transiently reduces plasma glucose and insulin levels.

Animals↗

PubMed1986

Effect of inhibitors of the FAD-containing monooxygenase system from rat liver microsomes on monomethylhydrazine metabolism and activation to reactive metabolites.

Several inhibitors of the FAD-containing monooxygenase (FAD-MO) system from rat liver microsomes (imipramine, chlorpromazine, mercaptoethylamine, dithiothreitol, naphthylthiourea, phenylthiocarbamide) and one inhibitor of the liver microsomal cytochrome P-450 (P-450)-mediated biotransformations (SKF 525 A), were tested as possible inhibitors of monomethylhydrazine (MMH) biotransformation to CO2 and to reactive metabolites that bind covalently to nucleic acids and proteins. Results confirm previous suggestions that both FAD-MO and P-450 are involved in MMH metabolism to CO2 and suggest a similar participation of both systems for production of reactive metabolites interacting with macromolecules.

Animals↗

PubMed1990

A microcytofluorometric method for quantitative and qualitative evaluation of CFU-E and BFU-E colonies.

A new method has been developed for the precise identification of human bone marrow colony forming unit erythroid (CFU-E) and burst forming unit erythroid (BFU-E) colonies, and for determination of the hemoglobin contents using microcytofluorometry. The method relies on a photochemical reaction in which intracellular hemoglobin is converted into fluorescent porphyrin under violet light (lambda = 405 nm) in the presence of an SH-donor (mercaptoethylamine hydrochloride). The CFU-E and BFU-E colonies showed red fluorescence with two spectrum peaks at 600 and 650 nm when illuminated by violet light. These two peaks are consistent with those of porphyrin fluorescence. The porphyrin fluorescence was not inducible in colony forming unit granulocyte-macrophage (CFU-GM) colonies, while 20% of the CFU-GM colonies were false positive with respect to the conventional benzidine reaction. The photochemically inducible fluorescence began to appear in BFU-E colonies on the 4th day of culture, while the same colonies started to be positive for the benzidine reaction on the 9th day. Therefore, the photochemical reaction was more specific and sensitive than the benzidine reaction for the identification of CFU-E and BFU-E colonies. In addition, this method enabled us to measure the hemoglobin level in the cells forming the colonies because the intensity of the fluorescence was proportional to the amount of hemoglobin when the photochemical reaction was carried out for 50 min.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗

PubMed1977

Cytofluorometric analysis of cell proliferation and differentiation of the human erythroblasts.

The method of cytofluorometric measurement of the contents of Hb and nuclear DNA on a single erythroid cell (Fukuda et al., l975; 1977a) was used for the quantitative analysis of the erythropoiesis in normal bone marrow. The intracellular Hb in an erythroid cell was converted to fluorescent porphyrin after removing the Giemsa staning by irradiation with violet light in the presence of SH-donor (mercaptoethylamine hydrochloride, MEA) and its nuclear DNA was subsequently stained with pararosaniline Feulgen staining. With the two quantitative parameters, Hb content and DNA amount, the erythroid cells in normal human bone marrow were classified into 6 classes of different maturation stages (EI-EIV). The morphological characteristics of the most primitive erythroblast (EI cells) were described. The "proerythroblasts" which were identified on the bases of morphological criteria had in general aneuploid amounts of nuclear DNA with disproportional contents of Hb, thereby indicating that they are rather aberrations from the normal steps of cell maturation. The DNA amounts of "orthochromatic erythroblasts" (EV cells) showed continuous decrease from diploid range to almost zero suggesting that the removal of nuclear DNA from the erythroblast is not exclusively due to mechanical explusion of a whole intact nucleus.

Adult↗

PubMed1991

Products of the reaction of selenite with intracellular sulfhydryl compounds.

The usual first step in the intracellular metabolism of exogenous selenite is its chemical reaction with glutathione to form selenodiglutathione (1). We have investigated whether selenite also reacts intracellularly with other SH compounds. HeLa cells were exposed to [75Se]selenite and lysed with SDS. Cellular proteins and nucleic acids were precipitated with trichloroacetic acid, and the acid-soluble fraction was analyzed by ion-exchange thin-layer chromatography (ion-exchange TLC) and autoradiography. In control cells, the major [75Se]-containing species detected can be identified by its mobility as selenodiglutathione. Two other species were detected, which can be identified as selenodimercaptoethylamine and the mixed selenotrisulfide of mercaptoethylamine and glutathione. In contrast, in cells that were depleted of glutathione (by treatment with buthionine sulfoximine), very little, if any, selenodiglutathione was detected. However, new [75Se]-containing species were detected, which can be identified as selenodicysteine and the mixed selenotrisulfide of cysteine and glutathione. The same species were detected when [75Se]selenite was added to the acid-soluble fraction of a cell extract (as opposed to living cells), confirming that these compounds can be formed by nonenzymatic reactions.

Antimetabolites↗

PubMed1999

An electrochemical study of the factors responsible for modulating the reduction potential of putidaredoxin.

The gene coding for putidaredoxin has been synthesized using a combination of chemical and enzymatic methods and subsequently expressed in Escherichia coli. The recombinant protein characterized by electronic spectroscopy, mass spectrometry, and electrochemistry was found to be identical to putidaredoxin obtained from Pseudomonas putida. Polylysine was found to promote the fast and reversible electrochemistry of putidaredoxin at negatively charged electrodes such as indium-doped tin oxide or gold surfaces modified with mercaptoalkanoate groups. The value of the heterogeneous electron transfer rate constant obtained from solutions containing a mixture of putidaredoxin and polylysine (k(s) = 1.3 x 10(-3) cm/s) is one order of magnitude larger than the values reported previously at gold electrodes modified with mercaptoethylamine or at antimony-doped tin oxide semiconductor electrodes. It was observed that when the reduction potential of putidaredoxin is measured by cyclic voltammetry, the resultant value is consistently more positive (64 mV) than the reduction potential measured with potentiometric titrations. A comparison between the electrochemical responses of putidaredoxin and spinach ferredoxin, combined with the examination of their corresponding three-dimensional structures, indicates that the positive shift in the reduction potential of putidaredoxin originates from the formation of a transient complex between putidaredoxin and polylysine at the electrode surface. The formation of this transient complex modulates the reduction potential of putidaredoxin by lowering the value of the dielectric constant around its iron-sulfur cluster microenvironment, specifically by neutralizing negative charges surrounding the active site and by excluding water from the solvent exposed iron sulfur cluster. The observed positive shift in E degrees ', which is induced by complexation with polylysine at the electrode-surface, suggests that similar factors are likely to contribute to the anodic shift in the E degrees ' of cytochrome P450(cam)-bound putidaredoxin (+44 mV) with respect to the E degrees ' measured for free putidaredoxin.

Amino Acid Sequence↗

PubMed1986

Rat hepatic cholesterol 7 alpha-hydroxylase: biochemical properties and comparison to constitutive and xenobiotic-inducible cytochrome P-450 enzymes.

Cytochrome P-450Ch7 alpha (cholesterol 7 alpha-hydroxylase) catalyzes the first and rate-limiting step in the conversion of cholesterol to bile acids in mammalian liver. The properties of this cytochrome P-450 (P-450) form were studied in rat hepatic microsomal preparations in comparison to those of several well characterized constitutive and xenobiotic-inducible rat hepatic P-450s. Administration of the bile acid-sequestering resin cholestyramine [4% (w/w) in the diet] to male or female rats maintained on a reverse light cycle led to a 10- to 15-fold induction of P-450Ch7 alpha activity relative to untreated, standard light cycle controls. By contrast, the levels of four hepatic steroid hormone hydroxylating P-450 enzymes, designated 2a, 2c, 3, and PB-4 [Waxman, D.J. (1984) J. Biol. Chem. 259, 15481-15490], were not significantly affected by cholestyramine treatment. Antibody inhibition experiments established that P-450Ch7 alpha is immunochemically distinct from nine other rat hepatic P-450s, including P-450 3, a highly regio- and stereoselective steroid hormone 7 alpha-hydroxylase. P-450Ch7 alpha was shown to be selectively inactivated by micromolar concentrations of the disulfide-containing reagents disulfiram (Antabuse) and 2,2'-dithiopyridine. This inactivation was readily reversed upon incubation with 2-mercaptoethylamine, suggesting the presence of a highly reactive thiol group at the active site of P-450Ch7 alpha. These findings demonstrate that P-450Ch7 alpha corresponds to a unique P-450 enzyme exhibiting inductive, biochemical, immunochemical, and regulatory properties distinct from those of nine well-characterized rat hepatic P-450 forms.

2,2'-Dipyridyl↗

PubMed1995

A novel strategy affords high-yield coupling of antibody Fab' fragments to liposomes.

A new assay for the production of reactive sulfhydryl-bearing antibody Fab' fragments has been utilized to develop conditions affording high efficiencies of coupling of mouse and rabbit IgG-derived Fab' fragments to lipid vesicles containing maleimidyl-functionalized phospholipids. Cysteine and mercaptoethylamine, but not dithiothreitol, reduce antibody F(ab')2 to Fab' fragments in very good yields under conditions where overreduction to heavy and light chains is minimized. Surprisingly, however, a large fraction of the Fab' fragments generated under these conditions can lack maleimide-reactive sulfhydryl groups, as demonstrated using a maleimidyl-poly(ethylene glycol) conjugate to shift selectively the electrophoretic mobility of the reactive sulfhydryl-bearing Fab' fragments. After modification of F(ab')2 reduction conditions specifically to maximize the yield of the latter fraction, it is possible to achieve high and very reproducible coupling of functional Fab' fragments to liposomes (equivalent to coupling of ca. 70% of total input protein and almost 100% of the reactive sulfhydryl-bearing Fab' fraction). A novel phospholipid-poly(ethylene glycol)-maleimide 'anchor' allows particularly efficient coupling of Fab' fragments to liposomes, even using relatively low liposome concentrations and molar percentages of the liposome-incorporated 'anchor' species. These results demonstrate that with appropriate optimization of the conditions for Fab' production and liposome coupling, Fab' fragments can be coupled to liposomes with efficiencies comparable to or exceeding those reported for coupling of intact antibodies. These results should facilitate the wider use of Fab' fragments as a potentially advantageous alternative to intact antibodies for liposomal targeting in various applications.

Animals↗

PubMed1975

Characterization of the collagen synthesized by cultured cartilage cells.

Cartilage cells from embryonic chick cartilage were grown in primary cultures. The cell layer was sequentially extracted with neutral saline, mercaptoethylamine and pepsin which revealed that these cells produced salt-soluble and salt-insoluble collagen. The alpha1- to alpha2-chain ratio was determined for the collagen extracted from the cultured cells and was found to be 13 to 1. Further analysis of the molecule was carried out by CNBr cleavage of the salt-extracted collagen and separation of resulting peptides by ion-exchange chromatography. It was shown that the cultured cartilage cells synthesize collagen of the type (alpha1[II])3.

Amino Acids↗

PubMed1985

The binding of the radioprotective agent cysteamine with the phospholipidic membrane headgroup-interface region.

The interaction of the aminothiol radioprotector cysteamine (beta-mercaptoethylamine) (CYST) with dipalmitoylphosphatidylcholine (DPPC) artificial membranes has been studied by differential scanning calorimetry (DSC), turbidimetry and spin labeling. This hydrophilic molecule displays a biphasic, concentration-dependent binding to the phospholipidic head groups at neutral pH. In the CYST/DPPC molar ratio 1:160-1:2 (mole/mole) an increasing ordering effect is observed. At high concentrations (over 3:1 ratio), this ordering effect decreases. With the symmetric disulfide dimer cystamine, the biphasic effect is not shown and the membrane rigidity decrease is obtained only at concentration ratio higher than 1:1. The charge repartition of the cysteamine molecule has been shown to be disymmetric, +0.52 e on the NH3 group and +0.19 e on the SH extremity, [38] whereas the cystamine molecule is electrostatically symmetrical. These properties could be related to their membrane effects. With cysteamine, at a low concentration, an electrostatic bridging between the negatively charged phosphate groups of the polar heads induces the increase in membrane stability: the molecules behave like a divalent cation. At high concentrations a displacement of the slightly charged SH extremity by the amine disrupts the bridges and induces the decrease in rigidity: the drug behaves like a monovalent cation. Due to its symmetric charge and its double length, such an effect is not observed with cystamine. This study could bring further information about the interactions between cysteamine and polyelectrolytic structures (ADN for example) and about the radioprotective properties of this drug.

Binding Sites↗

PubMed1988

Promotion of cystine uptake and its utilization for glutathione biosynthesis induced by cysteamine and N-acetylcysteine.

Chinese hamster ovary (CHO) cells obtain a high capacity to utilize cystine from the growth medium by exposure to cysteamine (2-mercaptoethylamine, MEA) or N-acetylcysteine (NAC). For uptake studies a modified McCoy's 5A medium supplemented with 0.1 mM [35S]cystine was used. The uptake of cystine was dependent on the time of exposure (0-60 min) and the concentrations of MEA or NAC (0-8 mM). At high concentrations of MEA or NAC, the uptake of cystine became saturated. Half-maximal uptake of cysteine was observed at concentrations of 0.12 mM MEA and 0.66 mM NAC, respectively. Increase in temperature (37-44 degrees) or pH (6.0-8.0) during MEA or NAC exposure further increased the cystine uptake. The increased uptake of cystine was not affected in the presence of glutamate or homocysteate which both inhibited the cystine uptake of control cells. Determination of both reduced (GSH) and oxidized (GSSG) cellular glutathione showed a twofold increase in MEA- or NAC-treated CHO cells. DL-buthionine-S,R-sulfoximine (BSO), an inhibitor of GSH biosynthesis completely blocked the promotion of cystine uptake by MEA and NAC. By further analysis using reversed-phase HPLC of cell extracts, more than 90% of the [35S] radioactive cystine taken up by the cells could be recovered within the pool of GSH. The results demonstrate that exposure of CHO cells with MEA and NAC leads to a promoted uptake of cystine from the culture medium and its rapid utilization for cellular GSH biosynthesis.

Acetylcysteine↗

PubMed1993

2-Mercaptoethanol is a survival factor for olfactory, cortical and hippocampal neurons in short-term dissociated cell culture.

A medium originally designed for lymphocyte growth promoted robust survival of olfactory receptor neurons (ORNs) in short-term (4-day), dissociated cell culture. The key ingredient for survival of neurons in both serum and serum-free conditions was 2-mercaptoethanol (2-ME). Enhancement of survival may be thiol-mediated because two other thiol compounds, 2-mercaptoethylamine and monothioglycerol, also increased ORN survival. Addition of 2-ME also significantly increased survival of embryonic cortical and hippocampal neurons in a serum-free medium, and embryonic cortical neurons in a serum-containing medium. After plating and growth in a serum-free medium containing 2-ME, survival of all three types of neurons was equivalent to, or greater than, survival in serum-containing media. Thus, thiols such as 2-ME promote the survival of multiple types of neurons in short-term cell culture.

Animals↗

PubMed1989

Structure-activity relationship of the preservation and restoration of glucocorticoid receptors in rat hepatocytes and rat liver homogenates by sulfhydryl, phosphorothioate and disulfide compounds.

The purpose of this work was to examine whether the ability of dithiothreitol to preserve the steroid-binding capacity of glucocorticoid receptors in subcellular preparations is specific or a general property of sulfhydryl compounds and selected phosphorothioate and disulfide derivatives. A further goal was to see if this effect could be demonstrated in intact cells. The ability to preserve the steroid-binding capacity of the glucocorticoid receptor is not a universal property of all sulfhydryl compounds since many of the compounds tested were inactive. The steroid-binding capacity of the glucocorticoid receptor of the 100,000 g supernatant of rat liver homogenate is preserved/restored by sulfhydryl compounds containing a mercaptoethylamine or mercaptopropylamine subunit. However, small changes in the structure of the sulfhydryl compound such as the rearrangement of a methylene group significantly alter its effectiveness. All of the phosphorothioates examined are derivatives of active sulfhydryl compounds and are effective in preserving steroid-binding. The extent of metabolism of the phosphorothioates and their failure to restore steroid-binding capacity after short-time exposure to receptor preparations are consistent with the sulfhydryl form being the active form of the phosphorothioates. S-2-(3-Amino-propylamino)ethylphosphorothioic acid (WR 2721) preserved steroid-binding capacity in isolated intact rat hepatocytes down to 25 microM demonstrating that concentrations obtainable in whole animals are effective with intact cells. Disulfide derivatives of active sulfhydryl compounds are either immediately toxic or ineffective except for 1,18-diamino-6,13-diaza-9,10-dithiaoctadecane (WR 149,024) which is more effective than its corresponding sulfhydryl. The demonstration that some sulfhydryl-forming compounds preserve the steroid-binding capacity of glucocorticoid receptors in intact cells at potentially physiologically obtainable concentrations suggests a potential role for these or similar compounds to bolster the efficacy of conventional glucocorticoid therapy.

Adrenalectomy↗

PubMed1988

Cysteamine-induced reduction in gastrointestinal somatostatin: evidence for a region-specific loss in immunoreactivity.

Administration of cysteamine (beta-mercaptoethylamine; 2-aminoethanethiol) to rats has been shown to decrease the levels of somatostatin-like immunoreactivity (SLI) in the gastrointestinal tract and pancreas but its mode of action is unclear. In the current study the effect of cysteamine on gastrointestinal and pancreatic SLI has been studied using two antisera with different regional specificities. In addition, the in vitro effect of cysteamine on SS-14 and SS-28 has been studied by high-performance liquid chromatography (HPLC). Characterization of the two antisera (AS 26.3.2 and AS 1001) with a range of analogs of SS-14 revealed that both were directed against the midportion of the molecule but that AS 1001 was also sensitive to changes at the N- and C-termini. Tissue extracts from cysteamine-treated rats measured with AS 26.3.2 showed no significant change for the stomach, jejunum or pancreas but duodenal levels were reduced. With AS 1001 SLI levels were reduced in all tissues. Gel permeation chromatography of stomach extracts measured with AS 1001 showed a reduction in both SS-14 and SS-28. With AS 26.3.2 an increase in SLI eluting prior to the SS-14 peak occurred explaining why no significant reduction in total SLI was detected. With duodenal extracts the elution profiles with AS 1001 reflected the large reduction in total SLI whereas with AS 26.3.2 a smaller reduction occurred. Both SS-14 and SS-28 were reduced. HPLC analysis of SS-14 and SS-28 following incubation with cysteamine in vitro showed a time-dependent decrease in both somatostatin species with absorbance at 280 nm was measured. New peptide peaks which developed were not all detectable by radioimmunoassay with either antibody. The results suggest that cysteamine causes a change in the structure of somatostatin which probably first involves a reduction of the disulphide bridge and then the N- and C-terminal regions of the molecule thus making it unmeasurable by antisera sensitive to changes in these regions.

Animals↗

PubMed1983

Further studies on age-related unusual catecholamine structures in brain.

The occurrence of large, intensely fluorescent (LIF) catecholamine-containing spots in the brains of mice and rats has been studied by fluorescence microscopy. LIF spots in C57BL/6J mice increased in number progressively with age. Apparent differences between sexes in the number of spots were not significant at any age. A greater number of LIF spots were present in older mice and rats of different strains indicating that LIF spot formation is neither strain nor species specific. Long-term feeding of antioxidants (ascorbic acid, alpha-tocopherol, and beta-mercaptoethylamine) to C57BL/6J mice did not alter significantly the number of LIF spots, suggesting that age-related LIF spots are formed by a mechanism other than endogenous free radical damage.

Age Factors↗

PubMed1990

Effects of cysteamine administration on plasma concentration of metabolites, pancreatic glucagon and insulin in the chicken.

1. The effects of subcutaneous injection of cysteamine (2-mercaptoethylamine, 300 mg/kg) were investigated in 5-6 week-old chickens. 2. In the short term (1 hr), cysteamine increased plasma levels of glucose, free fatty acids and insulin, and decreased that of alpha-amino non protein nitrogen. 3. In a longer term (17-24 hr), cysteamine increased the plasma level of glucose, did not modify those of alpha-amino non protein nitrogen, insulin and glucagon and decreased that of free fatty acids. 4. The disposal of an oral glucose load was impaired and the glucose-induced inhibition of pancreatic glucagon and stimulation of insulin release were blunted 17 hr after cysteamine administration. 5. Therefore, cysteamine exerts multiple effects on chicken pancreatic islet cells.

Animals↗

PubMedDate not supplied

Circumvention of the tumor membrane barrier to WR-2721 absorption by reduction of drug hydrophilicity.

In attempting to account for the ability of most solid tumors to restrict the absorption of WR-2721, aminopropyl-aminoethylphosphorothioate, we examined a number of drug characteristics which might allow for this restriction, and observed that drug hydrophilicity was a major contributing factor. When the highly hydrophilic WR-2721 was dephosphorylated, the drug became less hydrophilic and could readily cross tumor cell membranes. In addition, conventional radioprotectants, such as cysteine and mercaptoethylamine, were shown to be less hydrophilic than WR-2721 and also to cross tumor membranes readily. Therefore, drug hydrophilicity would appear to be the factor underlying the ability of WR-2721 to selectively protect normal tissues while most other protectors alter the radiation resistance of normal and tumor tissue alike. A red blood cell model for studying this problem in greater detail is described.

Absorption↗

PubMed1983

Prevention of thioacetamide-induced liver necrosis by prior administration of substrates of microsomal flavin-containing monooxygenase.

Prior administration of chlorpromazine (CPZ), imipramine (IMP), mercaptoethylamine (MEA), 1-(1-naphthyl)2-thiourea (ANTU) or phenyl-thiocarbamide (PTC) but not 1,4-dithio-1-threitol (DTT), was able effectively to prevent most of thioacetamide (TAC) -induced liver necrosis. These and previous observations suggest that liver microsomal flavin-containing monooxygenase critically controls the process of activation of TAC to the ultimate necrogen.

Acetamides↗