RESUMEN

Protectin D1 is a specialized pro-resolving mediator with potent pro-resolving and anti-inflammatory effects in vivo in several human disease models. Herein the preparation of the first synthetic analog of protectin D1, named 22-F-PD1, is presented together with data from in vivo investigations. This analog showed potent pro-resolving and anti-inflammatory properties. These results inspired the preparation of the radiotracer 22-[18F]F-PD1-ME that was used in a positron emission tomography proof of concept study. Altogether, the findings presented contribute to new knowledge on the biomolecular properties of protectin D1 analogs. In addition, an improved formal synthesis of the metabolite 22-OH-PD1 is reported.

Asunto(s)

Antiinflamatorios/síntesis química , Antiinflamatorios/farmacología , Ácidos Docosahexaenoicos/síntesis química , Ácidos Docosahexaenoicos/farmacología , Animales , Antiinflamatorios/química , Encéfalo/diagnóstico por imagen , Técnicas de Química Sintética , Ácidos Docosahexaenoicos/química , Humanos , Macrófagos/citología , Macrófagos/efectos de los fármacos , Ratones , Tomografía de Emisión de Positrones , Trazadores Radiactivos

RESUMEN

BACKGROUND: Epithelial ovarian cancer has a poor prognosis, mostly due to its late diagnosis and the development of drug resistance after a first platinum-based regimen. The presence of a specific population of "cancer stem cells" could be responsible of the relapse of the tumor and the development of resistance to therapy. For this reason, it would be important to specifically target this subpopulation of tumor cells in order to increase the response to therapy. METHOD: We screened a chemical compound library assembled during the COST CM1106 action to search for compound classes active in targeting ovarian stem cells. We here report the results of the high-throughput screening assay in two ovarian cancer stem cells and the differentiated cells derived from them. RESULTS AND CONCLUSION: Interestingly, there were compounds active only on stem cells, only on differentiated cells, and compounds active on both cell populations. Even if these data need to be validated in ad hoc dose response cytotoxic experiments, the ongoing analysis of the compound structures will open up to mechanistic drug studies to select compounds able to improve the prognosis of ovarian cancer patients.

Asunto(s)

Antineoplásicos/farmacología , Ensayos Analíticos de Alto Rendimiento , Células Madre Neoplásicas/efectos de los fármacos , Neoplasias Ováricas/tratamiento farmacológico , Bibliotecas de Moléculas Pequeñas/farmacología , Antineoplásicos/química , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Humanos , Estructura Molecular , Neoplasias Ováricas/patología , Bibliotecas de Moléculas Pequeñas/química , Relación Estructura-Actividad , Células Tumorales Cultivadas

RESUMEN

BACKGROUND: In breast cancer (BC) patients a cancer predisposing BRCA1/2 mutation is associated with adverse tumor characteristics, risk assessment and treatment allocation. We aimed to estimate overall- (OS) and disease-free survival (DFS) according to tumor characteristics and treatment among women who within two years of definitive surgery for primary BC were shown to carry a mutation in BRCA1/2 . MATERIAL AND METHODS: From the clinical database of the Danish Breast Cancer Group we included 141 BRCA1 and 96 BRCA2 BC patients. Estrogen receptor and HER2 status were centrally reviewed on paraffin-embedded tumor tissue. Information on risk reducing surgery was obtained from the Danish Pathology and Patient Registries and included as time-dependent variables in Cox proportional hazard models. RESULTS: Ten-year OS and DFS for BRCA1 BC patients were 78% (95% CI 69-85) and 74% (95% CI 64-81). Ten-year OS and DFS for BRCA2 BC were 88% (95% CI 78-94) and 84% (95% CI 74-91). BRCA1 BC patients as compared to BRCA2 BC patients had a higher risk of BC relapse or non-breast cancer within ten years of follow-up, independent of ER status (adjusted HR 2.78 95% CI 1.28-6.05, p = .01), but BRCA mutation was not associated with OS (adjusted HR 1.98, 95% CI 0.87-4.52, p = .10). In multivariate analysis, including both BRCA1 and BRCA2 carriers, no chemotherapy was associated with a higher risk of death (adjusted OS HR 3.58, 95% CI 1.29-9.97, p = .01) and risk reducing contralateral mastectomy (RRCM) was associated with a significantly reduced risk of death (adjusted OS HR 0.42, 95% CI =0.21-0.84, p = .01). CONCLUSION: Difference in OS between BRCA1 and BRCA2 BC patients could be ascribed to tumor-biology. BRCA1 BC patients may have a shorter ten-year DFS than BRCA2 BC patients. Chemotherapy and risk reducing contralateral mastectomy reduce mortality for both BRCA1 and BRCA2 BC patients.

Asunto(s)

Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias de la Mama/genética , Neoplasias de la Mama/mortalidad , Mutación , Adolescente , Adulto , Anciano , Neoplasias de la Mama/patología , Neoplasias de la Mama/terapia , Quimioterapia Adyuvante , Dinamarca/epidemiología , Supervivencia sin Enfermedad , Femenino , Predisposición Genética a la Enfermedad , Heterocigoto , Humanos , Mastectomía , Persona de Mediana Edad , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/patología , Sistema de Registros , Adulto Joven

RESUMEN

More than 400 million humans are estimated to be infected with the intestinal helminth parasite, Trichuris trichiura. The infection is chronic in nature and high-intensity infection can lead to colitis, anaemia, Trichuris Dysentery Syndrome and reduced cognitive performance. Single doses of 400 mg albendazole or 500 mg mebendazole (MBZ) are used in mass drug administration programmes, but this has been shown to be insufficient. In this study, worm expulsion dynamics are described after MBZ treatment, given as a multi-dose and single-dose treatment in two separate T. trichiura self-infection studies. Worm expulsion dynamics post-treatment showed a similar pattern regardless of the dose regime, with the first worms observed on day 2 and the last worms expelled on days 9 and 13 post-treatment. Establishment of a chronic infection was observed following the inefficient single-dose treatment. The prepatent period was 13-16 weeks in both studies and worms were found to have a lifespan of at least 1 year and 10 months. These self-infection studies provide key information on the chronicity of T. trichiura infections, expulsion dynamics after anthelmintic treatment and the prepatent period, as well as the fecundity of female worms, which was around 18,000 eggs/female per day.

Asunto(s)

Antihelmínticos/administración & dosificación , Heces/parasitología , Mebendazol/administración & dosificación , Recuento de Huevos de Parásitos , Tricuriasis/tratamiento farmacológico , Tricuriasis/parasitología , Trichuris/aislamiento & purificación , Adulto , Animales , Femenino , Humanos , Masculino , Factores de Tiempo , Resultado del Tratamiento

RESUMEN

A convergent stereoselective synthesis of the potent anti-inflammatory, proresolving and neuroprotective lipid mediator protectin D1 (2) has been achieved in 15% yield over eight steps. The key features were a stereocontrolled Evans-aldol reaction with Nagao's chiral auxiliary and a highly selective Lindlar reduction of internal alkyne 23, allowing the sensitive conjugated E,E,Z-triene to be introduced late in the preparation of 2. The UV and LC/MS-MS data of synthetic protectin D1 (2) matched those obtained from endogenously produced material.

Asunto(s)

Antiinflamatorios no Esteroideos/síntesis química , Ácidos Docosahexaenoicos/síntesis química , Lípidos/química , Animales , Antiinflamatorios no Esteroideos/química , Antiinflamatorios no Esteroideos/metabolismo , Ácidos Docosahexaenoicos/biosíntesis , Ácidos Docosahexaenoicos/química , Ratones , Estructura Molecular , Estereoisomerismo

RESUMEN

Patients with Birt-Hogg-Dube syndrome have an increased risk of developing hamartomas of the pilosebaceous unit, renal tumors of various types, lung cysts, and spontaneous pneumothorax. We present the case of a 54-year-old woman with a long history of whitish papules in the central region of the face and a family history of similar lesions. Biopsy and genetic study revealed a new mutation of the gene involved in Birt-Hogg-Dube syndrome.

Asunto(s)

Síndrome de Birt-Hogg-Dubé/genética , Mutación , Femenino , Humanos , Persona de Mediana Edad , Linaje

RESUMEN

Patients with Birt-Hogg-Dube syndrome have an increased risk of developing hamartomas of the pilosebaceous unit, renal tumors of various types, lung cysts, and spontaneous pneumothorax. We present the case of a 54-year-old woman with a long history of whitish papules in the central region of the face and a family history of similar lesions. Biopsy and genetic study revealed a new mutation of the gene involved in Birt-Hogg-Dube syndrome.

RESUMEN

OBJECTIVE: To identify whether a genetic variation (rs1800857; IVS1-5T>C) in the neuropeptide cholecystokinin-A receptor (CCKAR) gene is a risk factor in the pathogenesis of schizophrenia. METHOD: The variation was analysed in a case-control design comprising 508 patients with schizophrenia and 1619 control subjects. A possible functional impact of this variant on CCKAR protein synthesis through alterations in splicing was analysed in an exon-trapping assay. RESULTS: In males only, the risk variant, IVS1-5C, was associated with a significantly increased risk of schizophrenia. Carrying one risk allele was associated with an increased risk of 1.74 (Odds Ratio, OR) and homozygosity (CC) was associated with an OR of 3.19. The variation had no impact on protein synthesis of CCKAR. CONCLUSION: This is the first report associating the CCKAR gene variant with schizophrenia specifically in men. Our study strengthens the conclusion that a CCKAR dysfunction could be involved in the aetiology of schizophrenia.

Asunto(s)

Expresión Génica/genética , Intrones/genética , Receptor de Colecistoquinina A/genética , Esquizofrenia/genética , Adulto , Estudios de Casos y Controles , Cromosomas Humanos Par 4/genética , Dinamarca/epidemiología , Manual Diagnóstico y Estadístico de los Trastornos Mentales , Femenino , Humanos , Clasificación Internacional de Enfermedades , Masculino , Polimorfismo de Nucleótido Simple/genética , Sitios de Empalme de ARN/genética , ARN Mensajero/genética , Esquizofrenia/diagnóstico , Esquizofrenia/epidemiología , Índice de Severidad de la Enfermedad , Distribución por Sexo

RESUMEN

BACKGROUND: Blau syndrome is a chronic granulomatous disease with an autosomal dominant trait characterized by the triad granulomatous dermatitis, arthritis, and uveitis. It is caused by mutations in the NOD2 gene, also termed the CARD15 gene. OBJECTIVE: To report a novel mutation in the NOD2 gene associated with Blau syndrome. METHODS AND RESULTS: The proband was a 68-year-old ethnic Norwegian male who had uveitis and arthritis since 10 years of age followed by lifelong recurrent arthritis and chronic eye involvement. Genetic analysis showed a heterozygous c.1814 C>A, T605N mutation in NOD2 that has not previously been described. All of his three children had Blau syndrome and had inherited the NOD2 mutation. The proband's first son had exanthema, arthritis, and uveitis from 10 years of age and later presented with granulomatous lymphadenopathy, granulomatous parotitis, and granulomatous intestinal inflammation. The proband's daughter had arthritis, uveitis, and exanthema from 3 years of age. The proband's second son had uveitis, exanthema, and arthritis from 1.5 years of age. None of the cases had any involvement of the heart or lungs. CONCLUSION: We report a novel Blau syndrome-associated mutation with an autosomal dominant heritage. Most likely the mutation has arisen de novo in the proband. Genetic counselling and antenatal diagnostics should be available to the involved families.

Asunto(s)

Dermatitis/genética , Granuloma/genética , Proteína Adaptadora de Señalización NOD2/genética , Mutación Puntual , Enfermedades Cutáneas Genéticas/genética , Adolescente , Adulto , Anciano , Artritis/genética , Salud de la Familia , Femenino , Humanos , Masculino , Noruega , Linaje , Síndrome , Uveítis/genética

RESUMEN

Cholecystokinin (CCK) is a neuroendocrine peptide expressed in I-cells of the small intestine and in central and peripheral neurons. Whereas intestinal CCK is involved in the release of pancreatic enzymes and the contraction of the gallbladder, cerebral CCK is implicated in a variety of functions, such as feeding behaviour, anxiety and memory. The expression of CCK is developmentally regulated. Brain CCK mRNA levels are low before birth, but increase markedly shortly after birth and reach adult like patterns of expression three weeks after birth during the final maturation of the central nervous system. In the adult, several substances induce neuronal CCK mRNA expression via activation of transcription factors binding to regulatory elements in the CCK promoter. Recent studies have examined the signaling pathways, transcription factors and regulatory elements involved in cAMP, fibroblast growth factor-2, and calcium-induced CCK gene transcription in neuronal cells. The review describes the signaling pathways and transcription factors involved in neuronal CCK gene transcription.

Asunto(s)

Colecistoquinina/genética , Neuronas/metabolismo , Animales , Secuencia de Bases , Señalización del Calcio , AMP Cíclico/metabolismo , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , ADN/genética , Factor 2 de Crecimiento de Fibroblastos/metabolismo , Humanos , Modelos Neurológicos , Regiones Promotoras Genéticas , ARN Mensajero/genética , ARN Mensajero/metabolismo , Transducción de Señal , Factores de Transcripción/metabolismo , Transcripción Genética

RESUMEN

Cholecystokinin (CCK) is a neuropeptide expressed in the small intestine and in the central and peripheral nervous system. CCK gene expression is both spatially and temporally regulated. In neurons CCK production is increased by growth factors, cyclic adenosine 3', 5'-monophosphate (cAMP), dopamine, estrogen, and injury situations, while intestinal CCK expression is mainly regulated by food intake. The function of the proximal CCK promoter has been examined by transfection of human CCK-CAT reporter constructs in cultured cells, DNase I footprinting and gel shift assays. These studies have led to the identification of regulatory elements and transcription factors important for basal and stimulated gene expression and depicted the signaling pathways involved in growth factor and cAMP induced CCK transcription. The review outlines the current knowledge of the regulation of CCK transcription and describes the role of putative transcription factors in tissue-specific CCK gene expression.

Asunto(s)

Colecistoquinina/biosíntesis , Colecistoquinina/genética , Neuronas/metabolismo , Regiones Promotoras Genéticas , Transducción de Señal , Factores de Transcripción , Transcripción Genética , Animales , Secuencia de Bases , Células Cultivadas , Regulación de la Expresión Génica , Humanos , Modelos Biológicos , Datos de Secuencia Molecular , Homología de Secuencia de Ácido Nucleico , Transfección

RESUMEN

Cholecystokinin (CCK) is the most abundant neuropeptide in the mammalian brain, and in man significant quantities are expressed in all regions of the brain.1,2 Therefore, CCK has been implicated in a variety of CNS functions-such as feeding behavior, anxiety, analgesia and memory functions as well as psychiatric disease like panic disorder and schizophrenia (for review, see2,3). Recently, a number of studies have indicated that a C-36 to T transition in the CCK gene promoter Sp1 element4 (Figure 1) is associated with alcoholism and withdrawal symptoms as well as panic disorder.5-7 Moreover, it has been proposed that the polymorphism plays a direct role in the pathogenesis of the disorders by decreasing the expression and synthesis of CCK peptides. The significance of these findings is still unclear and other studies have failed to demonstrate linkage between the polymorphism and alcoholism.8 In this study we examined the function of the C-36 to T transition in transcription of the human CCK gene. We demonstrate that substitution of the C-36 residue causes a slight reduction of Sp1 and Sp3 binding, but this has no effect on transcription in vivo. Moreover, no difference in the response to physiological stimuli was observed. Taken together the results show that the C to T polymorphism does not play a direct role in the pathogenesis of either alcoholism or panic disorder and that a putative association to these disorders is likely to be the result of co-segregation with a linked mutation.

Asunto(s)

Química Encefálica/genética , Colecistoquinina/genética , Polimorfismo de Nucleótido Simple , Regiones Promotoras Genéticas/genética , Animales , Secuencia de Bases , Células Cultivadas , Drosophila , Regulación de la Expresión Génica , Genes Reporteros , Humanos , Datos de Secuencia Molecular , Plásmidos , Transfección

RESUMEN

The promoter of the cholecystokinin (CCK) gene possesses evolutionary conserved juxtaposed E-box and cAMP/TPA responsive elements (CRE/TRE). We have examined the functional interaction of these two sites. As previously noted, c-Jun/c-Fos heterodimers greatly increase promoter activity through association with the CRE/TRE. Mutation of the E-box enhanced the activation by c-Jun/c-Fos, as well as stimulation by forskolin and bFGF, that acts through the CRE/TRE site. Moreover, c-Jun/c-Fos stimulation was inhibited by co-expression of c-Myc and Max. The results indicate that factors associating with the E-box exhibit a negative cooperative effect on the activation via the CRE/TRE element. We propose that this mechanism plays a significant role in CCK gene transcription and other genes with juxtaposed E-box and CRE/TRE.

Asunto(s)

Colecistoquinina/genética , AMP Cíclico/metabolismo , Regulación de la Expresión Génica , Secuencias Hélice-Asa-Hélice , Leucina Zippers , Regiones Promotoras Genéticas , Elementos de Respuesta , Acetato de Tetradecanoilforbol/metabolismo , Animales , Secuencia de Bases , Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice , Factores de Transcripción con Cremalleras de Leucina de Carácter Básico , AMP Cíclico/farmacología , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/genética , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Humanos , Ratones , Datos de Secuencia Molecular , Mutagénesis , Proteínas Proto-Oncogénicas c-fos/genética , Proteínas Proto-Oncogénicas c-fos/metabolismo , Proteínas Proto-Oncogénicas c-jun/genética , Proteínas Proto-Oncogénicas c-jun/metabolismo , Proteínas Proto-Oncogénicas c-myc/genética , Proteínas Proto-Oncogénicas c-myc/metabolismo , Acetato de Tetradecanoilforbol/farmacología , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Células Tumorales Cultivadas

RESUMEN

Cholecystokinin (CCK) is a potent neuropeptide expressed in the small intestine and in the central nervous system. We have examined the effect of basic fibroblast factor (bFGF) and forskolin on CCK gene transcription and depicted the signaling pathways that lead to promoter activation. bFGF and forskolin stimulated promoter activity via a cAMP response element (CRE)/12-O-tetradecanoylphorbol-13-acetate response element (TRE) located 80 bp upstream from the transcription initiation site. In nuclear extracts from unstimulated as well as stimulated cells, only CRE-binding protein (CREB) and activating transcription factor-1 (ATF-1) bound to the CRE/TRE, and activation was associated with phosphorylation of CREB serine-133 and ATF-1 serine-63. In murine F9 cells, CREB stimulated promoter activity 10-fold in the presence of protein kinase A (PKA), and in SK-N-MC cells activation was inhibited 60-70% by a dominant negative CREB mutant. In contrast, ATF-1 had no effect in F9 cells and exhibited a dominant negative effect in SK-N-MC cells. bFGF stimulation led to phosphorylation of the p38 mitogen-activated protein kinase (MAPK), and the extracellular signal-regulated kinase (ERK) MAPK and promoter activation, phosphorylation of CREB, and GAL4-CREB-dependent transcription were selectively prevented by a dominant negative Ras-mutant, the p38 MAPK-specific inhibitor SB203580, and the MAP/ERK kinase 1 (MEK1) inhibitor PD098059. Forskolin stimulation proceeded via the PKA pathway, and to a minor extent via the p38 and ERK MAPK pathways. We conclude that bFGF and forskolin stimulate the CCK gene promoter via the CRE/TRE(-80) in the proximal promoter region. Signaling proceeds through the p38 MAPK, the ERK MAPK, and the PKA-signaling pathways, which leads to cumulative phosphorylation and activation of CREB. We propose that bFGF in combination with neurotransmitters/neuropeptides coupling to the PKA-signaling pathway play an important role in the control of CCK gene expression.

Asunto(s)

Proteínas Quinasas Dependientes de Calcio-Calmodulina/metabolismo , Colecistoquinina/genética , Proteína Receptora de AMP Cíclico/metabolismo , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Proteínas de Unión al ADN , Proteínas Quinasas Activadas por Mitógenos , Factor de Transcripción Activador 1 , Secuencia de Bases , Proteínas Portadoras , Colecistoquinina/efectos de los fármacos , Colecistoquinina/metabolismo , Colforsina/metabolismo , Colforsina/farmacología , Proteína Receptora de AMP Cíclico/efectos de los fármacos , Factor 2 de Crecimiento de Fibroblastos/metabolismo , Factor 2 de Crecimiento de Fibroblastos/farmacología , Regulación de la Expresión Génica/efectos de los fármacos , Genes ras/fisiología , Humanos , Datos de Secuencia Molecular , Fosforilación , Regiones Promotoras Genéticas/efectos de los fármacos , Elementos de Respuesta , Transducción de Señal , Factores de Transcripción/metabolismo , Transcripción Genética , Proteínas Quinasas p38 Activadas por Mitógenos

Asunto(s)

Daño Encefálico Crónico/inducido químicamente , Solventes/efectos adversos , Humanos , Enfermedades Profesionales/inducido químicamente

RESUMEN

We have examined cis-elements and trans-acting factors that regulate transcription of the human cholecystokinin (CCK) gene. Transient expression of CCK promoter deletion constructs in human SK-N-MC neuroblastoma cells depicted positive cis-elements between the positions -100 to -92, -84 to -74, and -58 to -37, 5' to the transcription initiation site. Correspondingly, DNase I protection analysis showed that transacting factors bound to elements within these regions. The sequences encompass a putative basic helix-loop-helix leucine zipper (bHLH-ZIP) element, an Sp1 element, and a combined cAMP- and TPA-responsive element (CRE/TRE) at positions -97 to -92, -39 to -34, and -80 to -73, respectively. Mobility and supershift assays demonstrated that upstream stimulatory factor (USF) and Sp1 bind to the former elements and competition experiments confirmed that CREB/ATF and AP-1 bind to the CRE/TRE element. Mutation of the bHLH-ZIP and CRE/TRE elements decreased the activity of the promoter by 65% and 42%, respectively. The activity of the promoter was increased six- and two-fold after stimulation with forskolin and TPA, respectively. Stimulation was eliminated after mutation of the CRE/TRE element. Co-transfection experiments with pRSV-c-jun, pSV-fos, and pRC-RSV-CREB constructs showed that jun, CREB, and AP-1 stimulate transcription. We conclude that USF, Sp1, and members of the CREB/ATF and AP-1 family of transcription factors are the major determinants of CCK gene transcription.

Asunto(s)

Colecistoquinina/genética , Factor de Transcripción Sp1/genética , Factor de Transcripción AP-1/genética , Activación Transcripcional , Secuencia de Bases , Eliminación de Gen , Secuencias Hélice-Asa-Hélice/genética , Humanos , Datos de Secuencia Molecular , Células Tumorales Cultivadas

RESUMEN

Various aspects of enzyme-catalysed racemate resolution are discussed by using examples from hydrolysis of butanoates of glycerol derivatives. Primary esters of various 1,2-ketals gave low enantioselectivity (E). The results with secondary esters varied. The highest E value (> 100) was obtained when the primary ether groups were methyl and phenylethyl. For the corresponding methyl, phenyl diether E was observed to increase as the hydrolysis proceeded. The stereochemistry of the products agree with a proposed model for lipases.

Asunto(s)

Butiratos/química , Glicerol/análogos & derivados , Lipasa/metabolismo , Butiratos/metabolismo , Ácido Butírico , Glicerol/metabolismo , Preparaciones Farmacéuticas/síntesis química , Estereoisomerismo , Especificidad por Sustrato

Asunto(s)

Eritrocitos/efectos de los fármacos , Hemólisis/efectos de los fármacos , Vanadio/farmacología , Humanos , Técnicas In Vitro , Peróxidos Lipídicos/sangre

RESUMEN

Pentavalent vanadium (V5) as Na48VO3 was given i.p. to male Wistar rats at a dose of 5 mumol/kg in order to study its organ distribution pattern. Two days after injection, kidneys reached a V level of about 28 nmol/g wet weight, followed in decreasing order by spleen, liver, bone, blood plasma, testis, lung, erythrocytes and brain in control rats. A similar distribution pattern was seen after injection of tetravalent vanadium (V4) given as 48VOSO4. Two chelators, desferrioxamine B (Desferal) or Ca-Na3-diethylene triamine pentaacetic acid (DTPA), were given i.p. 24 h after the vanadium injections to different groups of rats at two dosage levels, 30 and 100 mumol/kg. Desferal (30 mumol/kg) reduced the vanadium content of the kidney by 17%, of the liver by 0%, and of the lung by 7%. The corresponding figures for the effect of DTPA (30 mumol/kg) were 7%, plus 15%, and 0%, respectively. At 100 mumol/kg, Desferal reduced the same organ levels by 20%, 26%, and 25%, respectively, and DTPA by 9%, 18%, and 25%, respectively. Both chelators raised faecal excretion at the low level, and both urinary and faecal excretion at the high level. Spleen and bone seemed to bind vanadium to a higher degree than the other organs under examination. Human erythrocytes, when incubated with 48VOSO4 (V4) or Na48VO3 (V5), were found to accumulate nearly the double amount of V5 as compared to V4. Glutathione (GSH) which is the main reducing substance within the erythrocytes, reduced the uptake of V5 to the V4 level when incubated together with GSH before addition to the cell suspension. Pretreating the erythrocytes with diethyl-maleate (DEM) which blocks the reducing SH groups of intracellular GSH, also reduced the uptake of V5. This may indicate a GSH dependent reduction of V5 to V4 within the erythrocytes. Four chelators, among them Desferal and DTPA, were found to reduce the cellbound amount of vanadium, either by extracting vanadium as V4, or by inhibiting uptake by the red blood cells.

Asunto(s)

Quelantes/farmacología , Eritrocitos/metabolismo , Vanadio/metabolismo , Animales , Humanos , Técnicas In Vitro , Masculino , Ratas , Ratas Endogámicas , Distribución Tisular , Vanadatos