RESUMO
Proteasome activation has been shown to promote cellular and organismal healthspan and to protect against aggregation-related conditions, such as Alzheimer's disease (AD). Various natural compounds have been described for their proteasome activating properties but scarce data exist on marine metabolites that often possess unique chemical structures, exhibiting pronounced bioactivities with novel mechanisms of action. In this study, we have identified for the first time a marine structural proteasome activator, namely (1R,3E,6R,7Z,11S,12S)-dolabella-3,7,18-trien-6,17-olide (DBTO). DBTO activates the 20S proteasome complex in cell-free assays but also in cellulo. Continuous supplementation of human primary fibroblasts with DBTO throughout their cellular lifespan confers an improved healthspan while ameliorated health status is also observed in wild type (wt) Caenorhabditis elegans (C. elegans) nematodes supplemented with DBTO. Furthermore, treatment of various AD nematode models, as well as of human cells of neuronal origin challenged with exogenously added Aß peptide, with DBTO results in enhanced protection against Aß-induced proteotoxicity. In total, our results reveal the first structural proteasome activator derived from the marine ecosystem and highlight its potential as a compound that might be used for healthspan maintenance and preventive strategies against proteinopathies, such as AD.
Assuntos
Doença de Alzheimer , Proteínas de Caenorhabditis elegans , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Animais , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Ecossistema , Humanos , Complexo de Endopeptidases do Proteassoma/metabolismo , Trientina/metabolismo , Trientina/farmacologiaRESUMO
Wilson disease is an autosomal recessive genetic disorder caused by loss-of-function mutations in the P-type copper ATPase, ATP7B, which leads to toxic accumulation of copper mainly in the liver and brain. Wilson disease is treatable, primarily by copper-chelation therapy, which promotes copper excretion. Although several de-coppering drugs are currently available, their Cu(I)-binding affinities have not been quantitatively characterized. Here we determined the Cu(I)-binding affinities of five major de-coppering drugs - D-penicillamine, trientine, 2,3-dimercapto-1-propanol, meso-2,3-dimercaptosuccinate and tetrathiomolybdate - by exploring their ability to extract Cu(I) ions from two Cu(I)-binding proteins, the copper chaperone for cytochrome c oxidase, Cox17, and metallothionein. We report that the Cu(I)-binding affinity of these drugs varies by four orders of magnitude and correlates positively with the number of sulfur atoms in the drug molecule and negatively with the number of atoms separating two SH groups. Based on the analysis of structure-activity relationship and determined Cu(I)-binding affinity, we hypothesize that the endogenous biologically active substance, α-lipoic acid, may be suitable for the treatment of Wilson disease. Our hypothesis is supported by cell culture experiments where α-lipoic acid protected hepatic cells from copper toxicity. These results provide a basis for elaboration of new generation drugs that may provide better therapeutic outcomes.
Assuntos
Quelantes/metabolismo , Cobre/metabolismo , Hepatócitos/citologia , Ácido Tióctico/farmacologia , Apoptose/efeitos dos fármacos , Proteínas de Transporte/metabolismo , Linhagem Celular , Proliferação de Células , Quelantes/farmacologia , Cobre/toxicidade , Proteínas de Transporte de Cobre , Hepatócitos/efeitos dos fármacos , Degeneração Hepatolenticular/tratamento farmacológico , Humanos , Metalotioneína/metabolismo , Penicilamina/metabolismo , Penicilamina/farmacologia , Ácido Tióctico/uso terapêutico , Trientina/metabolismo , Trientina/farmacologiaRESUMO
The API triethylenetetramine dihydrochloride used as an alternative treatment of Wilson's disease is sensitive to water and it exhibits polymorphism. As this may become an issue for the drug formulation, the physical stability has been studied by differential scanning calorimetry, high-pressure thermal analysis, dynamic vapor sorption, and X-ray diffraction as a function of temperature. In addition, high-pressure liquid chromatography and mass spectrometry have been used to study the purity and chemical stability of the API. A pressure-temperature phase diagram of the pure compound has been constructed and it can be concluded that form II is monotropic in relation to form I, which is the only stable solid. The solubilities of the different solid forms have been determined with the help of a temperature - composition phase diagram. The API is very soluble, at 20° C about 10% of the saturated solution with respect to the dihydrate consists of API and the solubility of the pure form I is twice as high. Moreover, it has been shown that at 20°C, a relative humidity above 40% induces the formation of the dihydrate and at 70% a saturated solution appears. At higher temperatures, the formation of the dihydrate appears at lower relative humidity values. A clear link has been established between the API's chemical stability, its physical stability and the relative humidity in the air. Humidity levels above 40% are detrimental to the quality of the API.
Assuntos
Trientina/química , Trientina/metabolismo , Varredura Diferencial de Calorimetria/métodos , Estabilidade de Medicamentos , Espectroscopia de Ressonância Magnética/métodos , SolubilidadeRESUMO
Several nucleic acid components and their metal complexes are known to be involved in crucial metabolic steps. Therefore the study of metal-nucleic acid interactions becomes essential to understand these biological processes. In this work, the synthetic purine-like nucleoside acyclovir (acv) has been used as a model of guanosine recognition with copper(II)-polyamine chelates. The chemical stability of the N9-acyclic arm in acv offers the possibility to use this antiviral drug to deepen the knowledge of metal-nucleoside interactions. Cu(II) chelates with cyclam, cyclen and trien were used as suitable receptors. All these copper(II) tetraamine chelates have in common the potential ability to yield a Cu-N7(apical) bond assisted by an appropriate (amine)N-Hâ¯O6(acv) intra-molecular interligand interaction. A series of synthesis afforded the following compounds: [Cu(cyclam)(ClO4)2] (1), {[Cu(cyclam)(µ2-NO3)](NO3)}n (2), {[Cu(cyclam)(µ2-SO4)]·MeOH}n (3), {[Cu(cyclam)(µ2-SO4)]·5H2O}n (4), [Cu(cyclen)(H2O)]SO4·2H2O (5), [Cu(cyclen)(H2O)]SO4·3H2O (6), [Cu(trien)(acv)](NO3)2·acv (7) and [Cu(trien)(acv)]SO4·0.71H2O (8). All these compounds have been characterized by X-ray crystallography and FT-IR spectroscopy. Our results reveal that the macrochelates Cu(cyclen)(2+) and Cu(cyclam)(2+) are unable to bind acv at an apical site. In contrast, the Cu(trien)(2+) complex has proved to be an efficient receptor for acv in compounds (7) and (8). In the ternary complex [Cu(trien)(acv)](2+), the metal binding pattern of acv consists of an apical Cu-N7 bond assisted by an intra-molecular (primary amino)N-Hâ¯O6(acv) interligand interaction. Structural comparisons reveal that this unprecedented apical role of acv is due to the acyclic nature of trien together with the ability of the Cu(trien)(2+) chelate to generate five-coordinated (type 4+1) copper(II) complexes.
Assuntos
Aciclovir/química , Complexos de Coordenação/química , Cobre/química , Poliaminas/química , Aciclovir/metabolismo , Antivirais/química , Antivirais/metabolismo , Quelantes/química , Quelantes/metabolismo , Complexos de Coordenação/metabolismo , Cobre/metabolismo , Cristalografia por Raios X , Ciclamos , Compostos Heterocíclicos/química , Compostos Heterocíclicos/metabolismo , Modelos Moleculares , Conformação Molecular , Estrutura Molecular , Nucleosídeos/química , Nucleosídeos/metabolismo , Poliaminas/metabolismo , Purinas/química , Purinas/metabolismo , Espectroscopia de Infravermelho com Transformada de Fourier , Termogravimetria , Trientina/química , Trientina/metabolismoRESUMO
Amine-containing compounds including polymers, oligomers and small molecules, without conventional fluorophores, are found to emit strong visible fluorescence after a one-step heat treatment. Furthermore, our results demonstrate for the first time that not only tertiary amine groups but also primary and secondary amine groups can act as fluorescent moieties.
Assuntos
Aminas/química , Corantes Fluorescentes/química , Corantes Fluorescentes/metabolismo , Temperatura Alta , Microscopia Confocal , Cebolas/citologia , Células Vegetais/metabolismo , Polímeros/química , Espectrometria de Fluorescência , Trientina/química , Trientina/metabolismoRESUMO
Triethylenetetramine (TETA; Syprine; Merck Rahway, NJ), a drug for Wilson's disease, is a copper chelator and a charge-deficient analog of polyamine spermidine. We recently showed that TETA is metabolized in vitro by polyamine catabolic enzyme spermidine/spermine-N(1)-acetyltransferase (SSAT1) and by thialysine acetyltransferase (SSAT2) to its monoacetylated derivative (MAT). The acetylation of TETA is increased in SSAT1-overexpressing mice compared with wild-type mice. However, SSAT1-deficient mice metabolize TETA at the same rate as the wild-type mice, indicating the existence of another N-acetylase respons 2ible for its metabolism in mice. Here, we show that siRNA-mediated knockdown of SSAT2 in HEPG2 cells and in primary hepatocytes from the SSAT1-deficient or wild-type mice reduced the metabolism of TETA to MAT. By contrast, 1,12-diamino-3,6,9-triazadodecane(SpmTrien), a charge-deficient spermine analog, was an extremely poor substrate of human recombinant SSAT2 and was metabolized by SSAT1 in HEPG2 cells and in wild-type primary hepatocytes. Thus, despite the similar structures of TETA and SpmTrien, SSAT2 is the main acetylator of TETA, whereas SpmTrien is primarily acetylated by SSAT1.
Assuntos
Acetiltransferases/metabolismo , Espermina/análogos & derivados , Trientina/metabolismo , Animais , Células Cultivadas , Hepatócitos/enzimologia , Hepatócitos/metabolismo , Camundongos , Proteínas Recombinantes/metabolismo , Espermina/metabolismoRESUMO
Triethylenetetramine (TETA) dihydrochloride, or trientine, is a therapeutic molecule that has long been used as a copper-chelating agent for the second-line treatment of patients with Wilson's disease. More recently, it has also been employed as an experimental therapeutic molecule in diabetes where it improves cardiac structure in patients with diabetic cardiomyopathy and left-ventricular hypertrophy. TETA is metabolized by acetylation, which leads to the formation of two main metabolites in humans and other mammals, monoacetyl-TETA (MAT) and diacetyl-TETA (DAT). These metabolites have been identified in the plasma and urine of healthy and diabetic subjects treated with TETA, and could themselves play a role in TETA-mediated copper chelation and restoration of physiological copper regulation in diabetes. In this regard, a potentiometric and spectrophotometric study of Cu(II)-complex formation equilibria of TETA, MAT and DAT is presented here, to provide a comprehensive evaluation of the stoichiometries of the complexes formed and of their relative stability constants. A potentiometric study has also been conducted on the corresponding Zn(II) complexes, to evaluate any possible interference with TETA-mediated Cu(II) binding by this second physiological transition-metal ion, which is present in similar concentrations in human plasma and which also binds to TETA. An ESI-MS study of these systems has both confirmed the complex formation mechanisms established from the potentiometric and spectrophotometric results, and in addition provided direct information on the stoichiometry of the complexes formed in solution. These data when taken together show that the 1 : 1 complexes formed with Cu(II) and Zn(II) have different degrees of protonation. The stability of the Cu(II) and Zn(II) complexes with the three ligands, evaluated by the parameters pCu and pZn, decreases with the introduction of the acetyl groups. Nevertheless the stability of Cu(II) complexes with MAT is sufficiently high to enable its participation in copper scavenging from the patient. A speciation study of the behavior of TETA and MAT with Cu(II) in the presence of Zn(II) at peri-physiological plasma concentrations is also presented. While Zn(II) did not hinder copper binding, the possibility is raised that prolonged TETA treatment could possibly alter the homeostatic regulation of this essential metal ion. The lack of reliable literature stability constants concerning the Cu(II) and Zn(II) interaction with the major transport proteins in plasma is also briefly considered.
Assuntos
Complexos de Coordenação/química , Cobre/química , Trientina/metabolismo , Zinco/química , Humanos , Concentração de Íons de Hidrogênio , Íons/química , Ligantes , Concentração Osmolar , Prótons , Espectrometria de Massas por Ionização por Electrospray , Espectrofotometria Ultravioleta , Trientina/química , Trientina/urinaRESUMO
Triethylenetetramine (TETA) is an efficient copper chelator that has versatile clinical potential. We have recently shown that spermidine/spermine-N(1)-acetyltransferase (SSAT1), the key polyamine catabolic enzyme, acetylates TETA in vitro. Here, we studied the metabolism of TETA in three different mouse lines: syngenic, SSAT1-overexpressing, and SSAT1-deficient (SSAT1-KO) mice. The mice were sacrificed at 1, 2, or 4 h after TETA injection (300 mg/kg i.p.). We found only N(1)-acetyltriethylenetetramine (N(1)AcTETA) and/or TETA in the liver, kidney, and plasma samples. As expected, SSAT1-overexpressing mice acetylated TETA at an accelerated rate compared with syngenic and SSAT1-KO mice. It is noteworthy that SSAT1-KO mice metabolized TETA as syngenic mice did, probably by thialysine acetyltransferase, which had a K(m) value of 2.5 ± 0.3 mM and a k(cat) value of 1.3 s(-1) for TETA when tested in vitro with the human recombinant enzyme. Thus, the present results suggest that there are at least two N-acetylases potentially metabolizing TETA. However, their physiological significance for TETA acetylation requires further studies. Furthermore, we detected chemical intramolecular N-acetyl migration from the N(1) to N(3) position of N(1)AcTETA and N(1),N(8)-diacetyltriethylenetetramine in an acidified high-performance liquid chromatography sample matrix. The complex metabolism of TETA together with the intramolecular N-acetyl migration may explain the huge individual variations in the acetylation rate of TETA reported earlier.
Assuntos
Acetiltransferases/metabolismo , Trientina/metabolismo , Acetilação , Acetiltransferases/genética , Animais , Cromatografia Líquida , Fígado/enzimologia , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Camundongos , Camundongos Endogâmicos C57BL , Camundongos KnockoutRESUMO
The selective Cu(II)-chelator, triethylenetetramine (TETA), is undergoing clinical trials for the treatment of heart failure in patients with diabetes. Recently, the authors showed that 2 acetylated metabolites, N(1)-acetyltriethylenetetramine (MAT) and N(1),N(10)-diacetyltriethylenetetramine (DAT), are formed in humans following oral TETA administration. Thus, it became necessary to determine whether the N-acetyltransferase (NAT) 2 phenotype has any effects on the pharmacological properties and safety profile of TETA. Twelve fast and 12 slow NAT2-phenotype healthy participants were recruited. After oral drug administration, the authors collected plasma and urine samples, measured plasma concentrations of TETA and its 2 metabolites along with concomitant urinary copper concentrations, and performed safety tests. They present, for the first time, the complete 24-hour pharmacokinetic profiles of TETA, MAT, and DAT in humans. There was no evidence for clear-cut differences in pharmacokinetic profiles between fast and slow acetylators. Pharmacodynamic analysis showed no significant differences in cupruresis between the 2 NAT2 phenotypes. Safety results were consistent with TETA being well tolerated, and no significant differences in safety profiles were observed between the 2 phenotypes. Based on these data, NAT2 phenotype does not affect TETA's pharmacokinetic, pharmacodynamic, or safety profiles. TETA may be acetylated via an alternative mechanism, such as that catalyzed by spermidine/spermine N(1)-acetyltranferase.
Assuntos
Quelantes/farmacologia , Quelantes/farmacocinética , Trientina/metabolismo , Trientina/farmacologia , Trientina/farmacocinética , Adulto , Arilamina N-Acetiltransferase/genética , Quelantes/efeitos adversos , Cobre/urina , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Fatores de Tempo , Trientina/efeitos adversos , Trientina/análogos & derivados , Trientina/sangueRESUMO
Earlier studies revealed that age-associated iron accumulation plays an important causal role in osteopenic development after estrogen deficiency. It is believed that an increase in iron content is associated with an increased likelihood of oxidative damage at the point of iron accumulation. However, there is no direct evidence that the iron accumulated in skeletal tissue causes free radical oxidative damage and consequent bone loss. Iron depletion from skeletal tissues of ovariectomized (OVX) rats was carried out with the oral chelator [1-N-docosyl-triethylenetetraminepentaacetic acid (DoTTPA)]. Results suggest the causal role of iron in oxidative damage that may lead to bone loss in the rats. The results also show the therapeutic potential of the bone-targeted chelator to protect against bone loss associated with age-iron accumulation as well as iron overload diseases.
Assuntos
Acetatos/uso terapêutico , Quelantes de Ferro/uso terapêutico , Ferro/metabolismo , Músculo Esquelético/metabolismo , Osteoporose Pós-Menopausa/metabolismo , Osteoporose Pós-Menopausa/prevenção & controle , Trientina/análogos & derivados , Acetatos/administração & dosagem , Acetatos/química , Acetatos/metabolismo , Animais , Espectroscopia de Ressonância de Spin Eletrônica , Feminino , Radicais Livres/metabolismo , Humanos , Quelantes de Ferro/metabolismo , Estresse Oxidativo , Ratos , Ratos Sprague-Dawley , Trientina/administração & dosagem , Trientina/química , Trientina/metabolismo , Trientina/uso terapêuticoRESUMO
A validated method for the determination of triethylenetetramine, a selective copper-chelator currently undergoing clinical trials for the treatment of diabetic heart failure, and its two major metabolites, N(1)-acetyltriethylenetetramine and N(1),N(10)-diacetyltriethylenetetramine in human serum using HPLC is reported. The method used 9-flouorenylmethylchloroformate chloride to label all three analytes. The fluorescence labeled analytes were then separated chromatographically using a reversed phase C18 column under a gradient elution program and detected spectrofluorometrically at 317 nm with excitation at 263 nm. Application of the method is demonstrated by pharmacokinetic measurement in one healthy volunteer taking the drug orally.
Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Trientina/sangue , Estabilidade de Medicamentos , Humanos , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Trientina/análogos & derivados , Trientina/metabolismoRESUMO
Triethylenetetramine (TETA), a selective Cu(II)-chelator used in the treatment of Wilson's disease, is now undergoing clinical trials for the treatment of heart failure in diabetes. Despite decades of clinical use, knowledge of its pharmacology in human subjects remains incomplete. Here, we first used liquid chromatography-mass spectrometry (LC-MS) to detect and identify major metabolites of TETA in human plasma and urine, and then used this method to measure concentrations of TETA and its metabolites in the urine of healthy and diabetic subjects who were administered increasing doses (300, 600, 1200, and 2400 mg) of TETA orally. Twenty-four-hour urine collections were performed before and after dosing participants. Two major metabolites of TETA were detected in human urine, N(1)-acetyltriethylenetetramine (MAT) and N(1),N(10)-diacetyltriethylenetetramine, the latter being novel. Both metabolites were verified with synthetic standards by LC-MS. The proportion of unchanged TETA excreted as a fraction of total urinary drug-derived molecules was significantly higher in healthy than in matched diabetic subjects, consistent with a higher rate of TETA metabolism in the latter. TETA-evoked increases in urinary Cu excretion in nondiabetic subjects were more closely correlated with parent drug concentrations than in diabetic subjects, whereas, by contrast, urinary Cu was more closely associated with the sum of TETA and MAT. These findings are consistent with the hypothesis that MAT could play a significant role in the molecular mechanism by which TETA extracts Cu(II) from the systemic compartment in diabetic subjects.
Assuntos
Quelantes/metabolismo , Cobre/urina , Diabetes Mellitus Tipo 2/metabolismo , Trientina/urina , Zinco/urina , Adulto , Idoso , Humanos , Masculino , Pessoa de Meia-Idade , Trientina/metabolismoRESUMO
Selective application of metal chelators to homogenates of human Alzheimer's disease (AD) brain has led us to propose that the architecture of aggregated beta-amyloid peptide, whether in the form of plaques or soluble oligomers, is determined at least in part by high-affinity binding of transition metals, especially copper and zinc. Of the two metals, copper is implicated in reactive oxygen species generating reactions, while zinc appears to be associated with conformational and antioxidant activity. We tested the copper chelators trientine, penicillamine, and bathophenanthroline for their ability to mobilize brain Abeta as measured against our benchmark compound bathocuproine (BC). All of these agents were effective in solubilizing brain Abeta, although BC was the most consistent across the range of AD brain tissue samples tested. Similarly, all of the copper chelators depleted copper in the high-speed supernatants. BC alone had no significant effect upon zinc levels in the soluble fraction. BC extraction of brain tissue from C100 transgenic mice (which express human Abeta but do not develop amyloid) revealed SDS-resistant dimers as Abeta was mobilized from the sedimentable to the soluble fraction. NMR analysis showed that, in addition to its copper chelating properties, BC interacts with Abeta to form a complex independent of the presence of copper. Such hybrid copper chelating and "chain breaking" properties may form the basis of a rational design for a therapy for Alzheimer's disease.
Assuntos
Quelantes/farmacologia , Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/química , Peptídeos beta-Amiloides/efeitos dos fármacos , Peptídeos beta-Amiloides/metabolismo , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Quelantes/química , Quelantes/metabolismo , Cobre/química , Humanos , Camundongos , Camundongos Transgênicos , Ressonância Magnética Nuclear Biomolecular , Penicilamina/metabolismo , Penicilamina/farmacologia , Peptídeos/química , Peptídeos/efeitos dos fármacos , Peptídeos/metabolismo , Fenantrolinas/metabolismo , Fenantrolinas/farmacologia , Projetos Piloto , Solubilidade , Trientina/metabolismo , Trientina/farmacologia , Zinco/químicaRESUMO
Triethylene tetramine dihydrochloride (trien 2HCl) has been used for the treatment of Wilson's disease, which is characterized by the accumulation of copper in various organs. We previously developed an HPLC system for analyzing trien, and found a trien metabolite in the urine when trien was orally given to humans. In this study, the metabolite was identified as 1-N-acetyltriethylene tetramine (acetyltrien) by FAB-MS and 1H-NMR spectroscopy. Trien and acetyltrien were capable of combining with copper, iron and zinc. However, the chelating activity of acetyltrien was significantly lower than that of trien. When trien was given to healthy adults, the amount of trien excreted in the urine was about 1% of the administered trien, whereas that of acetyltrien was about 8%. Most of the trien was excreted within the first 6 hours after the administration, while acetyltrien was excreted for over 26 hours. The urinary copper, iron and zinc levels all increased in parallel with the trien excretion.
Assuntos
Quelantes/metabolismo , Trientina/metabolismo , Administração Oral , Adulto , Quelantes/farmacologia , Cromatografia Líquida de Alta Pressão , Cobre/metabolismo , Cobre/urina , Feminino , Humanos , Ferro/metabolismo , Ferro/urina , Espectroscopia de Ressonância Magnética , Masculino , Espectrometria de Massas de Bombardeamento Rápido de Átomos , Trientina/análogos & derivados , Trientina/farmacologia , Trientina/urina , Zinco/metabolismo , Zinco/urinaRESUMO
The uptake characteristics of trientine by rat intestinal brush-border membrane vesicles were studied. The uptake characteristics of trientine were similar to those of the physiological polyamines with respect to the excessive accumulation in vesicles, the pH dependency, the temperature dependency and the ineffectiveness of K+ diffusion potential (inside negative). The initial uptake of trientine was saturable with a K(m) value of 1.13 mM, which was larger than that of spermine and spermidine. Furthermore, the uptake rate of trientine was dose-dependently inhibited by spermine and spermidine. Spermine competitively inhibited the uptake of trientine with a Ki value of 18.6 microM, and it was close to the K(m) value for spermine (30.4 microM). These data suggested that the uptake of trientine was similar to that of spermine and spermidine in rat small intestinal brush-border membrane vesicles, and these polyamines seem to inhibit the absorption of trientine from the gastrointestinal tract.
Assuntos
Intestino Delgado/ultraestrutura , Trientina/metabolismo , Animais , Cromatografia Líquida de Alta Pressão , Difusão , Intestino Delgado/metabolismo , Masculino , Microvilosidades/metabolismo , Potássio/metabolismo , Ratos , Ratos Wistar , Espermidina/farmacologia , Espermina/farmacologia , Temperatura , Fatores de Tempo , Valinomicina/farmacologiaRESUMO
The relative abilities of a series of acyclic polyamine chelating agents containing only nitrogen donors (N-donors) to induce the urinary excretion of cadmium has been examined in the rat. The compounds examined include triethylenetetramine dihydrochloride (TRIEN), tris(2-aminoethyl)amine trihydrochloride (TREN), tetraethylenepentamine pentahydrochloride (TETRAEN), and pentaethylenehexamine hexahydrochloride (PENTAEN). Sodium N-methyl-D-glucamine-N-carbodithioate (NaG) was used as a positive control compound. The polyamines induced a significant increase in the urinary excretion of cadmium in rats that had been loaded with cadmium at least 4 d prior to the polyamine treatments. A comparison of these with similar data on macrocylic nitrogen donor systems, which form much more stable complexes with cadmium but are also ineffective in enhancing the excretion of cadmium from such aged deposits, suggests that the factors responsible for the relative inefficiency of these compounds may involve either a difficulty in penetrating cellular membranes or a slow rate of reaction with biologically bound cadmium. The occurrence of oliguria and anuria following the administration of the several of the polyamines indicates that their use is accompanied by significant renal damage in cadmium-exposed rats.
Assuntos
Cádmio/urina , Quelantes/farmacologia , Nitrogênio/metabolismo , Animais , Cádmio/toxicidade , Quelantes/metabolismo , Etilenodiaminas/química , Etilenodiaminas/metabolismo , Etilenodiaminas/farmacologia , Feminino , Rim/efeitos dos fármacos , Rim/patologia , Poliaminas/química , Poliaminas/metabolismo , Poliaminas/farmacologia , Ratos , Ratos Sprague-Dawley , Padrões de Referência , Sorbitol/análogos & derivados , Sorbitol/metabolismo , Sorbitol/farmacologia , Marcadores de Spin , Relação Estrutura-Atividade , Tiocarbamatos/metabolismo , Tiocarbamatos/farmacologia , Trientina/química , Trientina/metabolismo , Trientina/farmacologiaRESUMO
Triethylenetetramine (TETA) is the only available effective drug for the treatment of patients with Wilson's disease and with simultaneous intolerance to D-penicillamine. In the Ames-test, however both TETA and the structurally similar tetramine BE 6184 are mutagenic. The naturally occurring spermine, a closely related tetramine differing only in one additional methylene group in every carbon chain, shows no mutagenicity. TETA does not exhibit any mutagenic potency in the micronucleus-test.