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PubMed1966

Effects of cystamine and cysteamine on the adenosine-triphosphatase activity and oxidative phosphorylation of rat-liver mitochondria.

1. Cystamine (2,2'-diaminodiethyl disulphide) caused an unmasking of mitochondrial adenosine triphosphatase and a leakage of Mg(2+) from the mitochondria, and decreased the stimulation of adenosine triphosphatase by 2,4-dinitrophenol. When Mg(2+) was added, cystamine potentiated the activation of adenosine triphosphatase by 2,4-dinitrophenol. 2. Cystamine was without effect on the adenosine triphosphatase of disrupted mitochondria. 3. Cystamine was moderately potent as an uncoupling agent and as an inhibitor of the [(32)P]P(i)-ATP exchange reaction. 4. Cysteamine (2-aminoethanethiol) was without the above effects, when special precautions were taken to counteract its autoxidation. 5. The effects of cystamine should probably be ascribed to its disulphide group, since the diamine cadaverine protected slightly against the loss of Mg(2+) and the decrease of 2,4-dinitrophenol-stimulated adenosine-triphosphatase activity caused by aging of the mitochondria. It is suggested that cystamine acts by a breakdown of mitochondrial permeability barriers.

Adenosine Triphosphatases↗
PubMed2000

Radiation protection by cysteamine against the lethal effects of intracellularly localized Auger electron, alpha- and beta-particle emitting radionuclides.

The mechanisms by which DNA-incorporated radionuclides impart lethal damage to mammalian cells were investigated by examining the capacity of cysteamine (MEA) to protect against lethal damage to V79 cells caused by unbound tritium (3H2O), DNA-incorporated 131/125I-iododeoxyuridine (IdU) and the alpha-particle emitter 210Po-citrate. Radiolabeled cells were maintained at 10.5 degrees C for 72 h in the absence or presence of MEA (0.65-2.6 mM) and the surviving fraction was determined. Protection against lethal damage caused by 3H2O, 131IdU or 125IdU and 210Po-citrate depended on the concentration of MEA with maximum protection at 1.3-1.9 mM. The dose modification factors obtained at 1.3 mM for the radiochemicals were 2.5 +/- 0.3, 1.8 +/- 0.2, 1.7 +/- 0.1 and 1.4 +/- 0.1, respectively. MEA provides more protection against indirect than direct effects of ionizing radiation, and indirect effects play a role in the radiotoxicity of Auger electron emitters incorporated into the DNA of mammalian cells.

Animals↗
PubMed1975

Influence of rat blood on radiation protection of mammalian cells by cysteamine and cystamine in vitro.

The protective effect of cystamine and cystamine on T-cells in normal growth-medium was studied in the presence of whole rate blood (WRB). The protective effectiveness of both agents was increased by the addition of WRB, but much less so on the activity of cystamine. In the presence of WRB a dose-reduction factor of 1-5 was obtained at the low concentration of 0-05 mM cysteamine. The increase in protection was not due to induction of anoxia or to a release of glutathione from the rat red cell. The increase in protection may be due to protector RS radicals reacting with rat red cells.

Animals↗
PubMed1984

Effects of oxygen and sulphydryl-containing compounds on irradiated transforming DNA. II. Glutathione, cysteine and cysteamine.

This paper extends our earlier observations on the effects of the sulphydryl (SH)-containing compound dithiothreitol (DTT) on the radiation response of Bacillus subtilis transforming DNA to three other SH-containing compounds-cysteamine, cysteine and glutathione (GSH). In general, all four compounds protect transforming DNA in a manner which is dependent on gassing conditions. In O2, the protection is consistent with the scavenging of OH radicals by the SH compounds, but in N2 there is additional protection which may be due to hydrogen atom donation from the SH compound to radiation-induced DNA lesions, a process which is blocked by O2. This additional protection in N2 results in an increase in the ratio of inactivation in the absence and presence of oxygen with increasing SH concentration to a maximum followed by a decrease at high SH concentrations. The maximum value of the ratio and the SH concentration at which it occurs depend on the SH compound. In particular, GSH appears to be significantly less efficient in the hydrogen-donation repair reaction with transforming DNA than are the other three SH compounds. Furthermore, on the basis of our results, we postulate the existence of a damage fixation process which occurs in the absence of O2, in competition with damage repair by SH compounds, and that this anoxic damage fixation occurs at a rate not less than 300 s-1. We also demonstrate here that the damage fixing reaction of O2 with transforming DNA radicals proceeds 200-fold faster than the competing repair reaction by hydrogen-donation from DTT.

Bacillus subtilis↗
PubMed1998

EPR and spectrophotometric studies on free radicals (O2.-, Cysa-HB.-) and singlet oxygen (1O2) generated by irradiation of cysteamine substituted hypocrellin B.

PURPOSE: The aim of this work was to investigate the photodynamic action of cysteamine substituted hypocrellin B (Cysa-HB) photochemically and survey the effect of oxygen on its reaction mechanism. MATERIALS AND METHODS: The EPR method is used to detect the generation of the semiquinone anion radical of Cysa-HB (Cysa-HB.-), and active oxygen species using DMPO and TEMP as spin traps. DPA-bleaching method is used to determine the quantum yield of 1O2 generated from Cysa-HB photosensitization. RESULTS: In anaerobic solution, Cysa-HB.- was predominantly photoproduced via the self-electron transfer between the excited and ground state species. The presence of electron donors significantly promotes the reduced form of Cysa-HB. When oxygen-saturated solutions of Cysa-HB were illuminated with visible light, superoxide anion radical (O2.-) and singlet oxygen (1O2) were formed. The superoxide anion radical was generated by Cysa-HB.- via electron transfer to oxygen, and this process was significantly enhanced by the presence of electron donors. The 1O2 quantum yield is estimated to be 0.71. Moreover, the accumulation of 1O2 will be replaced by that of Cysa-HB.- with the depletion of oxygen. CONCLUSIONS: These observations suggest that the photodynamic action of Cysa-HB may proceed via both a Type I and Type II mechanism, and that a Type II mechanism will transform into a Type I mechanism as oxygen gets depleted.

Anions↗
PubMed2006

Effects of cysteamine on growth performance, digestive enzyme activities, and metabolic hormones in broilers.

A total of 600 avian male broilers at the age of 1 d were used to investigate the effects of cysteamine (CSH) on growth performance, digestive enzyme activities, and concentrations of serum hormones. The broilers received the same basal diets, with CSH added at 0 (control), 60, 90, 120, or 150 mg/kg. The feeding program consisted of a starter diet until 21 d and a grower diet until 42 d. The broilers with addition of CSH at 60 or 90 mg/kg had significantly higher growth rates during d 1 to 21 or d 21 to 42 compared with the control, respectively. However, adding 150 mg of CSH/kg significantly suppressed the growth of broilers. Adding 60 mg of CSH/kg significantly increased the activities of protease, amylase, and lipase in the pancreas and small intestinal contents during d 1 to 21, and the activities of protease and amylase in the small intestinal contents during d 21 to 42. Adding 90 mg of CSH/kg significantly increased the activities of lipase during d 1 to 21 and protease, amylase, and lipase during d 21 to 42 in small intestines. The activities of digestive enzymes during the whole period were suppressed by adding 150 mg of CSH/kg. The concentration of serum thyroxine was higher in the CSH-added birds during the whole period, whereas serum triiodothyronine was higher only during d 1 to 21 compared with the control. These findings indicate that low doses of dietary CSH may improve the growth performance and the activities of the digestive enzyme, but high doses of CSH appear to be detrimental to growth and digestion.

Aging↗
PubMed1992

Phase I trial of Perrimustine, a new cysteamine (2-chloroethyl) nitrosourea: an intrapatient escalation scheme.

The recently synthesized nitrosourea, N-[N'-chloro-2-ethyl-N'-nitrosocarbamoyl]-S-methyl cysteamine sulfoxide (Perrimustine), is water soluble and has a high alkylating activity, similar to that of the widely used nitrsoureas BCNU and CCNU, and a low carbamoylating activity. Preclinical studies with a broad spectrum of murine tumors indicate that this new compound may be clinically useful. The maximally efficient dose range (MEDR) in L1210 bearing mice was 45 mg/m2 (subcurative dose) to 67 mg/m2 (subtoxic dose). The present phase I trial used an intrapatient escalation schedule, so that each patient entering the study received a potentially active dose. The first dose injected was 1:100 of the MEDR suboptimal dose to check for anaphylactic sensitivity. Patients were then given increasing doses at increasing time intervals until toxicity was observed. The highest dose was given on day 150-230. The main toxic effect was myelosuppression [five out of the 24 patients evaluated: one grade 4 thrombocytopenia, two grade 3 thrombocytopenia; anemia and leucopenia were milder (grade 1 to 2 on OMS scale)]. Of the 19 patients evaluated for clinical response, one showed response after the 45 mg/m2 dose (disappearance of the cerebral metastasis with persistence of hepatic localizations in a patient with melanoma) and the disease was stabilized in two cases (a pleural mesothelioma and a renal carcinoma with lung metastases) after 26 and 37 weeks, with total cumulative doses per m2 of 232 and 196 mg, respectively.

Adolescent↗
PubMed1990

Role of accumulated gastric content in the pathogenesis of cysteamine- and mepirizole-induced duodenal ulcers in the rat.

Subcutaneous administration of cysteamine and mepirizole (at ulcerogenic and non- or weakly ulcerogenic doses) to fasted rats induced villous damage to the duodenum within 4 h. Only the damage induced by ulcerogenic doses progressed to macroscopically visible ulcers 10-12 h later. A considerable increase in gastric content was observed for more than 6-8 h after administration of the ulcerogenic dose of agents, but normal contents were noted 12 h later. The intraduodenal pH remained low for up to 16-20 h when ulcerogenic doses were given, but returned to control levels within 8-12 h when non-ulcerogenic doses were given. Histamine similarly caused villous damage to the duodenum, yet there was no progression to an ulcer. Accumulation of gastric contents and a lower intraduodenal pH with histamine persisted for only 2 h and 1 h, respectively. We conclude that prolonged accumulation of gastric contents for up to 8 h together with a decreased lower intraduodenal pH for 16-20 h are necessary for the developmental progression of villous damage to well-defined ulcers in the presence of ulcerogens.

Acid-Base Imbalance↗
PubMed1993

Role of the cellular stress response in the biogenesis of cysteamine-induced astrocytic inclusions in primary culture.

Cysteamine (CSH; 2-mercaptoethylamine) stimulates the accumulation of peroxidase-positive inclusions in cultured astroglia akin to those observed in the aging periventricular brain. Because CSH induces the synthesis of a stress protein (heme oxygenase) in rat liver, we hypothesized that aspects of the cellular stress response may play a role in the biogenesis of CSH-induced astrocyte granules. In the present study, we performed indirect immunofluorescent staining and immunoblotting for various stress proteins in rat neuroglial cultures. Exposure of astrocyte cultures to CSH enhanced immunostaining for heme oxygenase-1 (HO-1) and heat-shock proteins 27, 72, and 90, but not glucose-regulated protein 94, relative to untreated cultures. CSH-pretreated astrocytes exhibited enhanced tolerance to H2O2 toxicity relative to untreated cells, providing physiological evidence of an antecedent stress response in the former. In addition, exposure for 12 days to H2O2, a known inducer of the stress response, elicited astrocyte granulation similar to that observed with CSH. Chronic induction of HO-1 and other stress proteins may participate in the biogenesis of metalloporphyrin-rich inclusions in CSH-treated astroglial cultures and in astrocytes of the aging periventricular brain.

Animals↗
PubMed1958

The action of cysteamine and synkavit on gastric emptying in the normal and irradiated rat.

A radiographic method for studying the delay in gastric emptying in the rat caused by whole body irradiation has been applied to the investigation of two compounds which modify the effects of irradiation. The method may be of general use in the study of the action of drugs. Synkavit, which can potentiate the lethal effects of irradiation on tumours, caused a delay in gastric emptying. When Synkavit and irradiation were combined, a simple summation of the delays produced by each of these agents occurred. Cysteamine, which gives some protection against the lethal action of x-rays, also caused a delay in gastric emptying. It did not protect against the action of x-rays on stomach emptying.

Animals↗
PubMed2003

A multicentre randomised double masked clinical trial of a new formulation of topical cysteamine for the treatment of corneal cystine crystals in cystinosis.

AIM: To evaluate the safety and efficacy of a new topical cysteamine formulation, stable at room temperature, for the treatment of corneal cystine crystals in cystinosis. METHODS: 20 study subjects were enrolled in the safety study and 16 in the efficacy study. Both studies were randomised and double blind. The primary outcome for the safety study was the occurrence of predefined serious adverse reactions over 6 months and for the efficacy study the reduction of corneal cystine crystal score (CCCS) by 1.00 or more units on photographs graded by a reading centre using a standardised protocol. RESULTS: No study subject developed any serious adverse reactions. In the efficacy study, 47% of eyes receiving the standard formulation experienced a reduction in the CCCS of >/=1.00 after 1 year, while 7% of eyes on the new formulation experienced such a decrease (p=0.04). CONCLUSION: Although no serious adverse reactions were observed with either formulation, the new formulation was not as effective as the standard formulation.

Administration, Topical↗
PubMed1979

Comparison of the protective action of glutathione and cysteamine on radiation-induced mitotic delay in cultured S-5 cells.

The protective effect of glutathione (GSH) and cysteamine (MEA) on radiation-induced mitotic delay in cultured mammalian L-5 cells was studied. Cells treated with 20 mM of GSH during irradiation with 2 Gy (200 rad) showed faster recovery of the mitotic index than control cells irradiated without chemical treatment; however, GSH had no effect on mitotic delay time. Inhibition of mitosis was observed with 80, 100, and 120 mM of GSH. Cells treated with 5 mM of MEA during irradiation also showed faster recovery of the mitotic index than the controls, but in addition the delay time was shortened. Progression of G2-phase cells treated with 5-fluorouracil to mitosis after irradiation was protected by MEA but not by GSH. Progression of S-phase cells labeled with 3H-thymidine to mitosis was accelerated by both agents during irradiation.

Animals↗
PubMed1984

Cysteamine acts immediately to inhibit prolactin release and induce cellular changes in estradiol-primed male rats.

Cysteamine (CSH) has an inhibitory effect on the secretion of PRL, GH and TSH. The purpose of the present study was twofold: (1) to examine the short-term effects of CSH on PRL secretion, and (2) to elucidate the mechanism of action of CSH. CSH (100 mg/kg) was injected as an intra-atrial bolus to both normal and estradiol-primed male Sprague-Dawley rats. Blood samples were drawn every 2 min for 1 h and assayed for PRL. To determine if the actions of CSH involved PIF release or PIF receptors, a dopamine receptor blocking agent, pimozide (100 micrograms/kg) was given intra-atrially 1 h after the CSH injection and PRL concentration was monitored. Within 6 min after the CSH injection PRL levels in estradiol-primed rats began to fall, and by 30 min postinjection the levels were well below baseline values. Blocking the dopamine receptors with pimozide did not result in increased PRL levels, indicating that CSH was acting through some mechanism not directly involving dopaminergic PIF receptors. In a separate study, 6 min after the injection of CSH the rats were decapitated and their anterior pituitaries were removed and processed for electron microscopy. Only mammotrophs from estradiol-primed rats treated with CSH showed an extensive rearrangement of rough endoplasmic reticulum (RER) in concentric whorls around the periphery of the cells. These studies show that the inhibition of PRL secretion by CSH begins within 6 min, and is appreciable only when basal PRL levels are increased by estrogen priming.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1985

Cysteamine effects on monoamines, dopamine-beta-hydroxylase and the hypothalamic-pituitary axis.

Cysteamine (beta-mercaptoethylamine, MEA) is a naturally occurring sulfhydryl compound that depletes pituitary PRL, causes a reduction in brain and gut somatostatin (SRIF), and suppresses norepinephrine (NE) and epinephrine (EPI) synthesis by inhibition of dopamine-beta-hydroxylase (DBH). SRIF inhibits GH and TSH secretion, whereas, NE and EPI facilitate their release. The objectives of this investigation were to: (1) determine the dose-response and time course of DBH inhibition by MEA in vivo and in vitro, and correlate these findings with MEA tissue levels and (2) assess the function of SRIF and NE/EPI in regulation of episodic GH and TSH secretion using MEA. Animals were administered MEA (75-300 mg/kg, s.c.) and hypothalamic levels of dopamine (DA), NE, EPI, serotonin (5-HT) and MEA were measured by high-performance liquid chromatography (HPLC) and electrochemical detection. DBH activity was measured in vitro after exposure to MEA +/- N-ethylmaleimide (NEMI). Chronically cannulated rats were administered MEA (100 or 300 mg/Kg) and serial blood samples were removed in undisturbed animals, and after 30 min swimming stress. Cannulated rats with bilateral lesions of the ventromedial/arcuate nuclei (VMN/ARC) were administered MEA (150 mg/kg). MEA caused a dose-related decrease in NE/EPI nd in increase in DA at doses greater than or equal to 150 mg/kg. Tissue MEA was highest at 4 h (679 +/- 64 pM/mg tissue), but still measureable after 24 h. MEA inhibited DBH in vitro (95% inhibition at 10(-3) M); NEMI blocked inhibition. Stress-induced GH supression and corticosterone release were partially blocked by a low dose of MEA (100 mg/kg).(ABSTRACT TRUNCATED AT 250 WORDS)

3,4-Dihydroxyphenylacetic Acid↗
PubMed1988

Preferential interaction of [35S]cysteamine with pituitary secretory granule storage forms of prolactin.

Cysteamine (CySH) inhibits the immunodetectability and bioactivity of prolactin (PRL), and we have proposed that it may act by impeding the conversion from secretory granule hormone storage forms to releasable and assayable hormone. This process appears to be dependent upon thiol:disulfide interchange reactions, which can be inhibited by the aminothiol. The present studies utilized [35S]CySH to determine whether preferential interactions could be demonstrated between CySH and bovine pituitary storage hormone forms as opposed to monomeric PRL. [35S]CySH was incubated with purified intact secretory granules, with granule 'core' preparations enriched in oligomeric forms by prior hypotonic exposure, with chromatographically isolated oligomers, and with monomeric PRL. Binding to granules was saturable and pH-dependent with greatest binding observed at pH 7.5-8.0. Binding to monomer was much less than binding to all other fractions, being 20% or less than that to any other form. HPLC studies of granules treated with [35S]CySH indicated that exposure to CySH was associated with a predominance of very high molecular weight oligomers. These forms were entrapped on the gel permeation columns, resulting in decreased protein and PRL recovery; as little as 6.6% of the PRL was eluted after 60 min of CySH exposure. CySH not only bound to storage forms of PRL but also to secretory granule membranes; whether the bioeffect is mediated through membrane modifications is unknown. Despite its relative ineffectiveness at altering growth hormone immunoactivity or secretion, CySH nonetheless also bound to growth hormone.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Characterization of cysteamine induction of the 22K prolactin variant in the rat pituitary.

Glandular kallikrein (GK) is an estrogen-induced and dopamine-repressed lactotroph protease postulated to play a role in the processing of prolactin (PRL) to novel hormonal forms. Recent studies have shown that GK can process PRL in vitro from a 25K form to a 22K form in the presence of thiols--which appear to transform PRL into conformations (folding states) that are GK substrates. We and others have reported 22K PRL variants in the rat pituitary which can be increased by the administration of cysteamine (CSH), a biological thiol known to alter PRL conformation in vitro and in vivo. The present study further characterized CSH induction of the 22K PRL variant. Estrogen-primed rats were used in dose-response and time-course studies with CSH. CSH effects on 22K PRL levels were studied by Western blot analysis of reduced pituitary extracts (disulfides reduced with dithiothreitol before electrophoresis). Changes in PRL conformation were studied by Western blot analysis of nonreduced samples (thiols and disulfides trapped with iodoacetamide). CSH increased 22K PRL in a dose-dependent manner that was well correlated with the dose-response curve for changes in PRL conformation. CSH at 300 mg/kg produced 10- to 15-fold increases in pituitary levels of 22K PRL. In the time course study, 22K PRL levels peaked within 2 h, plateaued between 2 and 16 h, and approached control levels by 24 h after CSH dosing. CSH-elicited changes in PRL conformation peaked within 1 h, plateaued between 2 and 8 h, and reached control levels within 16 h of CSH dosing.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗
PubMed1994

Effect of cysteamine injection on vasopressin and oxytocin biosynthesis in rat hypothalamus.

Cysteamine (CSH), a sulfhydryl agent that promotes disulfide-exchange reactions, was studied for its effects on the immunoreactive (IR) levels and synthesis of oxytocin and vasopressin in the hypothalamus. CSH injection (300 mg/kg s.c.) caused a rapid (1 h) suppression of 35S-cysteine incorporation into hypothalamic arginine vasopressin (VP) and oxytocin (OT). The reduction in labeling persisted for about 8 h; label incorporation was normal within 10 h of CSH administration. The drug did not influence 35S-cysteine incorporation into acid-precipitable protein, nor did it influence 35S-cysteine specific activity in the hypothalamus. In addition, 35S-VP and 35S-OT molecules could not be recovered from hypothalami of CSH-treated rats by subjecting samples to denaturing, reducing and then reoxidizing conditions. Despite the reduction in peptide labeling, CSH treatment produced no alterations in the IR VP and OT contents of hypothalamus or posterior pituitary. These results indicate that CSH causes a true suppression of both VP and OT formation in hypothalamus, and suggest that the effect is either too transient to promote a reduction in endogenous stores of either peptide, or that the drug equally inhibits peptide production and removal (i.e., axonal transport, secretion).

Animals↗