RESUMEN
OBJECTIVE: Metastatic Crohn's disease is a rare and complex inflammatory condition distinguished by cutaneous granulomatous lesions outside the gastrointestinal tract. Genital involvement is rare; with less than 10 cases reported involving isolated penile lymphedema. Here, we present a case of isolated lymphedema of the penis as a consequence of extra-intestinal Crohn's disease. CASE REPORT: The patient is an 18-year-old African American male with a complex history of inflammatory bowel disease, who initially presented with a chief complaint of 6 weeks of swelling of his penis at age 13. A modified circumcision and lymphangectomy of the penis were performed; histopatholgy demonstrated a granulomatous infiltrate and interstitial edema of the distal penis. CONCLUSION: Surgical intervention is an applicable therapeutic alternative and last-line therapy for treatment of isolated penile lymphedema in select patients with appropriate pathology, and can be a suitable adjunct to medical management in these cases.
Asunto(s)
Enfermedad de Crohn/complicaciones , Linfedema/etiología , Enfermedades del Pene/etiología , Pene/patología , Adolescente , Enfermedad de Crohn/diagnóstico , Diagnóstico Diferencial , Humanos , Linfedema/diagnóstico , Masculino , Enfermedades del Pene/diagnósticoRESUMEN
Phlegmonous colitis is an acute suppurative infection of the large bowel that is rarely described, rapidly fatal and often escapes clinical attention. Patients with chronic hepatic diseases appear to be predisposed to this condition. We report a novel case of fatal phlegmonous colitis in a cirrhotic patient receiving combination pegylated interferon and ribavirin for chronic hepatitis C, highlighting the importance of early recognition of this aggressive infectious entity.
Asunto(s)
Colitis/diagnóstico , Hepatitis C Crónica/tratamiento farmacológico , Interferones/administración & dosificación , Ribavirina/administración & dosificación , Colitis/complicaciones , Quimioterapia Combinada , Resultado Fatal , Hepatitis C Crónica/complicaciones , Humanos , Masculino , Persona de Mediana EdadRESUMEN
We determined the orientation of the SDR (short-chain dehydrogenase/reductase) rat RoDH1 (retinol dehydrogenase type 1) in the endoplasmic reticulum to provide insight into its function in retinol metabolism, and to resolve whether retinoid-metabolizing SDRs differ from several other SDRs by requiring a C-terminal segment for the membrane orientation. In contrast to several soluble SDRs, the membrane-associated RoDH1 has hydrophobic extensions N- and C-terminal to the SDR core. Confocal microscopy and/or proteinase K protection assays of RoDH1, RoDH1 mutants, and RoDH1-green fluorescent protein fusion proteins showed that the N-terminal segment anchors RoDH1 to the endoplasmic reticulum membrane facing the cytosol. The C-terminal hydrophobic segment increases the relative proportion of RoDH1 associated with the endoplasmic reticulum, but has no affect on orientation. Deletion of either or both extensions causes nearly total loss of enzyme activity, possibly through altering the nature of RoDH1 association with membranes, or destabilizing the enzyme, but does not alter the expression of RoDH1 or convert it into a soluble protein. The latter suggests that the SDR core of RoDH1 has marked external hydrophobicity that causes nonspecific membrane association.
Asunto(s)
Oxidorreductasas de Alcohol/fisiología , Citosol/enzimología , Membranas Intracelulares/enzimología , Microsomas Hepáticos/enzimología , Fragmentos de Péptidos/fisiología , Transducción de Señal , Oxidorreductasas de Alcohol/química , Oxidorreductasas de Alcohol/genética , Secuencia de Aminoácidos , Animales , Células CHO , Cricetinae , Familia 2 del Citocromo P450 , Retículo Endoplásmico/enzimología , Retículo Endoplásmico/genética , Activación Enzimática/genética , Vectores Genéticos/síntesis química , Glicosilación , Interacciones Hidrofóbicas e Hidrofílicas , Datos de Secuencia Molecular , Fragmentos de Péptidos/química , Fragmentos de Péptidos/genética , Ratas , Proteínas Recombinantes de Fusión/biosíntesis , Transducción de Señal/genética , Transfección , Vitamina A/químicaRESUMEN
Mouse rdh6 encodes cis-retinoid/androgen dehydrogenase type 1 (CRAD1), a short-chain dehydrogenase, which recognizes as substrates 9-cis-retinol, 11-cis-retinol, 5 alpha-androstan-3 alpha,17 beta-diol and 5 alpha-androstan-3 alpha-ol-17-one, and is expressed most intensely in liver and kidney. The present study reports the genomic organization, chromosomal localization and promoter region sequence of rdh6. Rdh6 spans more than 38 kb and consists of four exons ranging from 164 to 2200 bp, and three introns ranging from 550 bp to greater than 18 kb. The gene localizes to the distal end of mouse chromosome 10, 72.5 cM from the centromere, and colocalizes with mouse rdh7, which encodes CRAD2. This corresponds to the locus of human rdh5 on human chromosome 12. Primer extension assays indicate two major transcription start sites in liver and one in kidney. The approximately 2000 kb sequenced of the 5'-flanking region contains multiple potential transcription factor binding sites, including sites for AP-1, C/EBP beta, GATA, c-Rel, ER, ROR alpha, SREBP, and CREB.
Asunto(s)
Oxidorreductasas de Alcohol/genética , Genes/genética , Regiones Promotoras Genéticas/genética , Región de Flanqueo 5'/genética , Animales , Secuencia de Bases , Sitios de Unión/genética , Mapeo Cromosómico , ADN/química , ADN/genética , Exones , Femenino , Intrones , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Datos de Secuencia Molecular , Muridae , Ratas , Análisis de Secuencia de ADN , Sitio de Iniciación de la TranscripciónRESUMEN
New York's (NY) Health Information Network (HIN) provided timely access to West Nile Virus (WNV) data during the initial outbreak in the late Summer 1999. In December 1999, NY developed a plan to deal with WNV in 2000 that required an integrated surveillance system for humans, birds, mammals, and mosquitoes. The HIN infrastructure allowed NY to deploy this system statewide in three months. Local health departments throughout NY used the system to report, track, and retrieve surveillance data as WNV spread throughout NY in 2000. The HIN infrastructure includes partnerships, training/support, technical capacity and architecture similar to NEDSS as proposed by the US CDC.
Asunto(s)
Aves/virología , Comunicación , Planificación en Desastres , Brotes de Enfermedades , Vigilancia de la Población/métodos , Fiebre del Nilo Occidental/prevención & control , Virus del Nilo Occidental/aislamiento & purificación , Animales , Humanos , New YorkRESUMEN
Metabolic activation of retinol (vitamin A) via sequential actions of retinol and retinal dehydrogenases produces the active metabolite all-trans-retinoic acid. This work reports cDNA cloning, enzymatic characterization, function in a reconstituted path of all-trans-retinoic acid biosynthesis in cell culture, and mRNA expression patterns in adult tissues and embryos of a mouse retinol dehydrogenase, RDH1. RDH1 represents a new member of the short chain dehydrogenase/reductase superfamily that differs from other mouse RDH in relative activity with all-trans and cis-retinols. RDH1 has a multifunctional catalytic nature, as do other short chain dehydrogenase/reductases. In addition to retinol dehydrogenase activity, RDH1 has strong 3alpha-hydroxy and weak 17beta-hydroxy steroid dehydrogenase activities. RDH1 has widespread and intense mRNA expression in tissues of embryonic and adult mice. The mouse embryo expresses RDH1 as early as 7.0 days post-coitus, and expression is especially intense within the neural tube, gut, and neural crest at embryo day 10.5. Cells cotransfected with RDH1 and any one of three retinal dehydrogenase isozymes synthesize all-trans-retinoic acid from retinol, demonstrating that RDH1contributes to a path of all-trans-retinoic acid biosynthesis in intact cells. These characteristics are consistent with RDH1 functioning in a path of all-trans-retinoic acid biosynthesis starting early during embryogenesis.
Asunto(s)
Oxidorreductasas de Alcohol/metabolismo , Hidroxiesteroide Deshidrogenasas/metabolismo , Vitamina A/metabolismo , Oxidorreductasas de Alcohol/química , Oxidorreductasas de Alcohol/genética , Secuencia de Aminoácidos , Animales , Secuencia de Bases , Línea Celular , Clonación Molecular , ADN Complementario , Embrión de Mamíferos/metabolismo , Hidroxiesteroide Deshidrogenasas/química , Hidroxiesteroide Deshidrogenasas/genética , Hibridación in Situ , Cinética , Ratones , Datos de Secuencia Molecular , ARN Mensajero/genética , ARN Mensajero/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
The mouse RALDH2 gene spans >50 kb, has a structure similar to that of human class 1 aldehyde dehydrogenase genes, and localizes to the central region of chromosome 9 by single-strand polymorphism analysis. Expression of mouse RALDH2 was detected in testis, lung, brain, and heart (Northern blot) and in liver and kidney (RNase protection assays). Expression was not detected by RNase protection assay in testis of vitamin A-deficient rats, and all-trans-retinoic acid dosing did not increase expression in vitamin A-deficient rat testis. A 2.3-kb section of the gene 5' to the transcription start site included neither retinoic acid nor retinoid X response elements, but included TATA and CCAAT motifs and AP, AHR, CREB, ER, Ets, and SREBP sites. The promoter initiated transcription of a luciferase reporter in human embryonic kidney cells (EBNA) and mouse Leydig- (TM3) and Sertoli-derived (TM4) cell lines, but neither all-trans-retinoic acid nor 9-cis-retinoic acid affected reporter transcription. These data suggest that relatively weak RALDH2 expression in vitamin A-deficient testis reflects vastly decreased numbers of germ cells, the major site of expression.
Asunto(s)
Aldehído Oxidorreductasas/biosíntesis , Aldehído Oxidorreductasas/genética , Regiones Promotoras Genéticas , Animales , Secuencia de Bases , Northern Blotting , Línea Celular , Mapeo Cromosómico , ADN Complementario/metabolismo , Riñón/metabolismo , Masculino , Ratones , Modelos Genéticos , Datos de Secuencia Molecular , Plásmidos/metabolismo , Polimorfismo Conformacional Retorcido-Simple , ARN/metabolismo , Ratas , Ratas Sprague-Dawley , Retinal-Deshidrogenasa , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Ribonucleasas/metabolismo , Testículo/metabolismo , Distribución Tisular , Transcripción Genética , Deficiencia de Vitamina A/genéticaRESUMEN
We examined expression of retinal dehydrogenase (RALDH) types 1 and 2 in liver and lung, and the effect of vitamin A status on testis expression by in situ hybridization. Liver expressed RALDH1 and RALDH2 only in stellate cells and hepatocytes, respectively. Lung expressed RALDH1 and RALDH2 throughout the epithelia of the airways, from the principal bronchi to the respiratory bronchiole. Vitamin A-sufficient rats expressed RALDH1 in spermatocytes, with less intense expression in spermatogonia and spermatids, and expressed RALDH2 in interstitial cells, spermatogonia, and spermatocytes. Neither Sertoli nor peritubular cells showed detectable RALDH1 or RALDH2 mRNA. Vitamin A deficiency produced a sevenfold increase in RALDH1 and a 70-fold decrease in RALDH2 mRNA in testis. In each case, the net change reflected extensive loss of germ cells, increased intensity of expression in residual germ cells, and expression in Sertoli and peritubular cells. Low-dose RA relatively early during vitamin A depletion supported spermatogenesis and affected expression of both RALDHs, but did not reinstate "vitamin A normal" expression patterns. These results show that: RALDH1 and RALDH2 have distinct mRNA expression patterns in multiple cell types in three vitamin A target tissues; RALDH expression occurs in cell types that express cellular retinol-binding protein and retinol dehydrogenase isozymes (except stellate cells, for which retinol dehydrogenase expression remains unknown); vitamin A deficiency and RA supplementation affects the loci and intensity of RALDH mRNAs in testis; and low-dose RA does not substitute completely for retinol. Overall, these data provide insight into the unique functions of RALDH1 and RALDH2 in retinoid metabolism.
Asunto(s)
Aldehído Oxidorreductasas/genética , Regulación Enzimológica de la Expresión Génica , Testículo/enzimología , Transcripción Genética , Deficiencia de Vitamina A/enzimología , Vitamina A/fisiología , Animales , Hepatocitos/enzimología , Hibridación in Situ , Isoenzimas/genética , Hígado/enzimología , Pulmón/enzimología , Masculino , ARN Mensajero/genética , Ratas , Ratas Sprague-Dawley , Retinal-Deshidrogenasa , Espermatocitos/enzimología , Espermatogénesis , Espermatogonias/enzimología , Testículo/citologíaRESUMEN
Subgroups of related short-chain dehydrogenase/reductase (SDR) family members serve as retinoid/androgen/estrogen metabolizing enzymes. These include retinol dehydrogenases (RoDHs) 1-3, cis-retinol/androgen dehydrogenase 1 and 2 (CRAD), retSDRs1-4, 9/11-cis-retinol dehydrogenase, and 17beta-hydroxysteroid dehydrogenase (17beta-HSD) types 6 and 9. Interaction with cellular retinol-binding protein (CRBP), the major physiological form of retinol, led to the identification and cDNA cloning of RoDH1. Probes for RoDH1 contributed to cDNA cloning many of the others. Some of these SDRs show specificity with all-trans-retinol (RoDH, retSDR, 17beta-HSD6 and 9) and others with 9 and/or 11-cis-retinol (CRAD, 9/11-cis-retinol dehydrogenase). Many have 3alpha-HSD activities with 3alpha-androstandiol as the most efficiently used substrate, followed by androsterone. In addition to 3alpha-HSD activity, CRAD2 shows relatively weak 17beta-HSD activity with testosterone. Rat 17beta-HSD6 and mouse 17beta-HSD9, which are not interspecies homologs, have efficient 17beta-HSD activities. 17beta-HSD6 has approximately 50% greater 17beta-HSD activity with estradiol than with 3alpha-androstandiol. With 3alpha-androstandiol, 17beta-HSD9 operates equally efficiently as a 17beta-HSD or a 3alpha-HSD. The multi-substrate nature of these SDRs allows for retinoid/steroid interactions. The ability of some these SDRs to access retinol bound with CRBP provides specificity in retinoid metabolism and allows retinoic acid biosynthesis and retinol esterification to continue, as CRBP protects retinol from the general cellular milieu.
Asunto(s)
17-Hidroxiesteroide Deshidrogenasas/metabolismo , Hidroxiesteroides/metabolismo , Isoenzimas/metabolismo , Retinoides/metabolismo , 17-Hidroxiesteroide Deshidrogenasas/química , Secuencia de Aminoácidos , Animales , Catálisis , Secuencia Conservada , Humanos , Datos de Secuencia Molecular , Filogenia , Homología de SecuenciaRESUMEN
This report describes the isolation of a heretofore uncharacterized aldehyde dehydrogenase (ALDH) with retinal dehydrogenase activity from rat kidney and the cloning and expression of a cDNA that encodes its human ortholog, the previously unknown ALDH12. The human ALDH12 cDNA predicts a 487-residue protein with the 23 invariant amino acids, four conserved regions, cofactor binding motif (G(209)XGX(3)G), and active site cysteine residue (Cys(287)) that typify members of the ALDH superfamily. ALDH12 seems at least as efficient (V(m)/K(m)) in converting 9-cis-retinal into the retinoid X receptor ligand 9-cis-retinoic acid as two previously identified ALDHs with 9-cis-retinal dehydrogenase activity, rat retinal dehydrogenase (RALDH) 1 and RALDH2. ALDH12, however, has approximately 40-fold higher activity with 9-cis- retinal than with all-trans-retinal, whereas RALDH1 and RALDH2 have equivalent and approximately 4-fold less efficiencies for 9-cis-retinal versus all-trans-retinal, respectively. Therefore, ALDH12 is the first known ALDH to show a preference for 9-cis-retinal relative to all-trans-retinal. Evidence consistent with the possibility that ALDH12 could function in a pathway of 9-cis-retinoic acid biosynthesis in vivo includes biosynthesis of 9-cis-retinoic acid from 9-cis-retinol in cells co-transfected with cDNAs encoding ALDH12 and the 9-cis-retinol/androgen dehydrogenase, cis-retinoid/androgen dehydrogenase type 1. Intense ALDH12 mRNA expression in adult and fetal liver and kidney, two organs that reportedly have relatively high concentrations of 9-cis-retinol, reinforces this notion.
Asunto(s)
Aldehído Deshidrogenasa/genética , Retinaldehído/metabolismo , Aldehído Deshidrogenasa/química , Aldehído Deshidrogenasa/metabolismo , Secuencia de Aminoácidos , Animales , Secuencia de Bases , Clonación Molecular , ADN Complementario , Diterpenos , Humanos , Riñón/enzimología , Masculino , Datos de Secuencia Molecular , ARN Mensajero/genética , Ratas , Ratas Sprague-Dawley , Retinaldehído/biosíntesis , TransfecciónRESUMEN
Continually expanding evidence has moved inexorably toward establishing key functions for cellular retinol-binding protein (CRBP) in retinoid metabolism. These experimental data integrate into a model of CRBP as a chaperone that protects retinol from the cellular milieu and interacts with certain retinoid-metabolizing enzymes. Mutant mice with an inactivated CRBP gene show decreased liver retinyl ester storage, a shorter elimination half-life of liver retinoids, and predisposition to vitamin A deficiency. No morphologic phenotype was observed until vitamin A was exhausted. Although the mechanisms underlying diminished vitamin A in the CRBP-null mice have not been elucidated, the observations support the model of CRBP as a chaperone of retinoid metabolism.
Asunto(s)
Aminoácidos/genética , Retinoides/metabolismo , Proteínas de Unión al Retinol/metabolismo , Aminoácidos/metabolismo , Animales , Ratones , Ratones Noqueados , Proteínas de Unión al Retinol/genética , Proteínas Celulares de Unión al Retinol , Vitamina A/metabolismoRESUMEN
The hallmarks of chronic liver diseases are chronic inflammation, cellular damage, regeneration and fibrosis. An appreciation of intrahepatic molecular expression patterns in normal and diseased liver provides clues for understanding pathogenic pathways whilst studies of the structure and function of molecules implicated in liver disease provide insights into their potential as therapeutic targets. We have examined the expression, function, molecular structure and structure-function relationships of type IV dipeptidyl aminopeptidases. In particular, the roles of CD26/DPPIV in T-cell proliferation and chemotaxis and of fibroblast activation protein in human cirrhosis are discussed. We have investigated the pathogenesis of liver disease by characterising patterns of cytokine and growth factor expression in experimental and human cirrhosis. We have quite recently expanded this approach to use differential gene expression analyses to elucidate overall pathways of gene activation and suppression in human cirrhosis. In addition, our detailed molecular and cellular studies of the mechanisms of spontaneous liver transplant tolerance have generated novel insights into this process. This review touches on these diverse aspects of liver function and disease.
Asunto(s)
Antígenos de Neoplasias , Biomarcadores de Tumor , Dipeptidil Peptidasa 4/fisiología , Hepatitis/enzimología , Cirrosis Hepática/enzimología , Hepatopatías/enzimología , Trasplante de Hígado , Subgrupos de Linfocitos T/enzimología , Adenosina Desaminasa/metabolismo , Animales , Apoptosis , Sitios de Unión , Diferenciación Celular , Citocinas/biosíntesis , Citocinas/genética , Dipeptidil Peptidasa 4/química , Endopeptidasas , Gelatinasas , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Supervivencia de Injerto , Sustancias de Crecimiento/biosíntesis , Sustancias de Crecimiento/genética , Sustancias de Crecimiento/fisiología , Hepatitis/inmunología , Hepatitis/patología , Humanos , Tolerancia Inmunológica , Cirrosis Hepática/inmunología , Cirrosis Hepática/patología , Hepatopatías/inmunología , Hepatopatías/patología , Trasplante de Hígado/inmunología , Activación de Linfocitos , Proteínas de la Membrana , Modelos Moleculares , Ratas , Serina Endopeptidasas/fisiología , Relación Estructura-Actividad , Técnica de Sustracción , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/patología , Células TH1/enzimología , Células TH1/inmunología , Células Th2/enzimología , Células Th2/inmunología , Activación TranscripcionalRESUMEN
PURPOSE: Occupational exposure to neutrons typically includes significant doses of low-energy neutrons, with energies below 100 keV. In addition, the normal-tissue dose from boron neutron capture therapy will largely be from low-energy neutrons. Microdosimetric theory predicts decreasing biological effectiveness for neutrons with energies below about 350 keV compared with that for higher-energy neutrons; based on such considerations, and limited biological data, the current radiation weighting factor (quality factor) for neutrons with energies from 10 keV to 100 keV is less than that for higher-energy neutrons. By contrast, some reports have suggested that the biological effectiveness of low-energy neutrons is similar to that of fast neutrons. The purpose of the current work is to assess the relative biological effectiveness of low-energy neutrons for an endpoint of relevance to carcinogenesis: in vitro oncogenic transformation. METHODS: Oncogenic transformation induction frequencies were determined for C3H10T1/2 cells exposed to two low-energy neutron beams, respectively, with dose-averaged energies of 40 and 70 keV, and the results were compared with those for higher-energy neutrons and X-rays. RESULTS: These results for oncogenic transformation provide evidence for a significant decrease in biological effectiveness for 40 keV neutrons compared with 350 keV neutrons. The 70 keV neutrons were intermediate in effectiveness between the 70 and 350 keV beams. CONCLUSIONS: A decrease in biological effectiveness for low-energy neutrons is in agreement with most (but not all) earlier biological studies, as well as microdosimetric considerations. The results for oncogenic transformation were consistent with the currently recommended decreased values for low-energy neutron radiation weighting factors compared with fast neutrons.
Asunto(s)
Transformación Celular Neoplásica , Fibroblastos/efectos de la radiación , Neutrones/efectos adversos , Animales , Línea Celular , Relación Dosis-Respuesta en la Radiación , Fibroblastos/citología , Análisis de los Mínimos Cuadrados , Funciones de Verosimilitud , Ratones , Efectividad Biológica RelativaRESUMEN
Interactions between all-trans-retinoic acid (RA) and bone morphogenetic proteins (BMPs) affect the expression of neurotrophin receptors in sympathetic neurons (Kobayashi et al., 1998). In this study, we examined the possibility that similar interactions might regulate the morphological development of these neurons. Under control conditions, embryonic rat sympathetic neurons formed axons but not dendrites; cells exposed to RA had a similar appearance. Profuse dendritic growth was observed upon exposure to BMP-7, and this was reduced by approximately 70% by RA. This inhibitory effect of RA was mediated primarily by retinoic acid receptors (RARs) and it exhibited substantial specificity because it was not associated with changes in either axonal elongation or cell survival. Moreover, mRNAs for enzymes required for synthesis of RA were expressed in the sympathetic neurons and retinoid activity was released from superior cervical ganglia. These observations suggest that retinoids may function as endogenous morphogens and regulate neural cell shape and polarity in developing sympathetic ganglia.
Asunto(s)
Neuronas/enzimología , Sistema Nervioso Simpático/enzimología , Sistema Nervioso Simpático/crecimiento & desarrollo , Factor de Crecimiento Transformador beta , Tretinoina/metabolismo , Oxidorreductasas de Alcohol/genética , Oxidorreductasas de Alcohol/metabolismo , Aldehído Oxidorreductasas/genética , Aldehído Oxidorreductasas/metabolismo , Animales , Axones/efectos de los fármacos , Axones/fisiología , Proteína Morfogenética Ósea 7 , Proteínas Morfogenéticas Óseas/antagonistas & inhibidores , Proteínas Morfogenéticas Óseas/farmacología , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Familia 2 del Citocromo P450 , Dendritas/efectos de los fármacos , Dendritas/fisiología , Relación Dosis-Respuesta a Droga , Embrión de Mamíferos , Humanos , Neuronas/citología , Neuronas/efectos de los fármacos , ARN Mensajero/biosíntesis , Ratas , Ratas Sprague-Dawley , Receptores de Ácido Retinoico/agonistas , Receptores de Ácido Retinoico/metabolismo , Retinal-Deshidrogenasa , Receptores X Retinoide , Ganglio Cervical Superior/citología , Ganglio Cervical Superior/enzimología , Ganglio Cervical Superior/crecimiento & desarrollo , Sistema Nervioso Simpático/citología , Sistema Nervioso Simpático/efectos de los fármacos , Factores de Transcripción/agonistas , Factores de Transcripción/metabolismo , Tretinoina/farmacología , Vitamina A/metabolismoRESUMEN
We report the characterization of two enzymes that catalyze NAD(+)-dependent 9-cis-retinol dehydrogenase activity in rat liver cystol. Alcohol dehydrogenase class I (ADHI) contributes > 80% of the NA D+-dependent 9-cis-retinol dehydrogenase activity recovered, whereas alcohol dehydrogenase class II (ADHII), not identified previously at the protein level, nor characterized enzymatically in rat, accounts for approximately 2% of the activity. Rat ADHII exhibits properties different from those described for human ADHII. Moreover, rat ADHII-catalyzed rates of ethanol dehydrogenation are markedly lower than octanol or retinoid dehydrogenation rates. Neither ethanol nor 4-methylpyrazole inhibits the 9-cis-retinol dehydrogenase activity of rat ADHII. We propose that ADHII represents the previously observed additional retinoid oxidation activity of rat liver cytosol which occurred in the presence of either ethanol or 4-methylpyrazole. We also show that human and rat ADHII differ considerably in enzymatic properties.
Asunto(s)
Alcohol Deshidrogenasa/metabolismo , Oxidorreductasas de Alcohol/metabolismo , Hígado/enzimología , Animales , Citosol/enzimología , Electroforesis en Gel de Poliacrilamida , Etanol/farmacología , Fomepizol , Humanos , Concentración de Iones de Hidrógeno , Isoenzimas/metabolismo , Cinética , Masculino , Pirazoles/farmacología , Ratas , Ratas Sprague-DawleyAsunto(s)
Familia/psicología , Holocausto/psicología , Trastornos por Estrés Postraumático/epidemiología , Sobrevivientes/estadística & datos numéricos , Adulto , Factores de Edad , Femenino , Humanos , Acontecimientos que Cambian la Vida , Masculino , Persona de Mediana Edad , Prevalencia , Trastornos por Estrés Postraumático/etiologíaRESUMEN
17Beta-hydroxysteroid dehydrogenases (17betaHSDs) convert androgens and estrogens between their active and inactive forms, whereas retinol dehydrogenases catalyze the conversion between retinol and retinal. Retinol dehydrogenases function in the visual cycle, in the generation of the hormone retinoic acid, and some also act on androgens. Here we report cloning and expression of a complementary DNA that encodes a new mouse liver microsomal member of the short chain dehydrogenase/reductase (SDR) superfamily and its enzymatic characterization, i.e. 17betaHSD9. Although 17betaHSD9 shares 88% amino acid identity with rat 17betaHSD6, its closest homolog, the two differ in substrate specificity. In contrast to other 17betaHSD, 17betaHSD9 has nearly equivalent activities as a 17betaHSD (with estradiol approximately = adiol) and as a 3alphaHSD (with adiol approximately = androsterone). It also recognizes retinol as substrate and represents in part the NAD+-dependent liver microsomal dehydrogenase that uses unbound retinol, but not retinol complexed with cellular retinol-binding protein. Thus, this enzyme has catalytic properties that overlap with two subgroups of SDR, 17betaHSD and retinol dehydrogenases. Inactivation of estrogen and a variety of androgens seems to be its most probable function. Because of its apparent inability to access retinol bound with cellular retinol-binding protein, a function in the pathway of retinoic acid biosynthesis seems less obvious. These data provide additional insight into the enzymology of estrogen, androgen, and retinoid metabolism and illustrate how closely related members of the SDR superfamily can have strikingly different substrate specificities.
Asunto(s)
17-Hidroxiesteroide Deshidrogenasas/genética , Oxidorreductasas de Alcohol/genética , Clonación Molecular , Isoenzimas/genética , 17-Hidroxiesteroide Deshidrogenasas/química , 17-Hidroxiesteroide Deshidrogenasas/metabolismo , Oxidorreductasas de Alcohol/química , Oxidorreductasas de Alcohol/metabolismo , Secuencia de Aminoácidos , Animales , Secuencia de Bases , Familia 2 del Citocromo P450 , ADN Complementario/genética , Inhibidores Enzimáticos/farmacología , Estradiol/metabolismo , Concentración de Iones de Hidrógeno , Isoenzimas/química , Isoenzimas/metabolismo , Ratones , Datos de Secuencia Molecular , NAD/farmacología , NADP/farmacología , Ratas , Especificidad por Sustrato , Tretinoina/metabolismo , Vitamina A/metabolismoRESUMEN
Dermatofibrosarcoma protuberans (DFSP) is a low grade, malignant spindle cell tumor with an infiltrative growth pattern and a high rate of local recurrence. This tumor's cell of origin is controversial. DFSP usually presents in adult life and is most frequently located on the trunk and proximal extremities. Although 10% to 15% of cases involve the head and neck, this tumor has not been previously described in the oral cavity.
Asunto(s)
Dermatofibrosarcoma/diagnóstico , Neoplasias de la Boca/diagnóstico , Adulto , Dermatofibrosarcoma/patología , Femenino , Humanos , Neoplasias de la Boca/patologíaRESUMEN
This article presents a model that integrates the functions of retinoid-binding proteins with retinoid metabolism. One of these proteins, the widely expressed (throughout retinoid target tissues and in all vertebrates) and highly conserved cellular retinol-binding protein (CRBP), sequesters retinol in an internal binding pocket that segregates it from the intracellular milieu. The CRBP-retinol complex appears to be the quantitatively major form of retinol in vivo, and may protect the promiscuous substrate from nonenzymatic degradation and/or non-specific enzymes. For example, at least seven types of dehydrogenases catalyze retinal synthesis from unbound retinol in vitro (NAD+ vs. NADP+ dependent, cytosolic vs. microsomal, short-chain dehydrogenases/reductases vs. medium-chain alcohol dehydrogenases). But only a fraction of these (some of the short-chain de-hydrogenases/reductases) have the fascinating additional ability of catalyzing retinal synthesis from CRBP-bound retinol as well. Similarly, CRBP and/or other retinoid-binding proteins function in the synthesis of retinal esters, the reduction of retinal generated from intestinal beta-carotene metabolism, and retinoic acid metabolism. The discussion details the evidence supporting an integrated model of retinoid-binding protein/metabolism. Also addressed are retinoid-androgen interactions and evidence incompatible with ethanol causing fetal alcohol syndrome by competing directly with retinol dehydrogenation to impair retinoic acid biosynthesis.
Asunto(s)
Tretinoina/metabolismoRESUMEN
Naturally occurring retinoids (vitamin A or retinol and its active metabolites) are vital for vision, controlling the differentiation program of epithelial cells in the digestive tract and respiratory system, skin, bone, the nervous system, the immune system, and for hematopoiesis. Retinoids are essential for growth, reproduction (conception and embryonic development), and resistance to and recovery from infection. The functions of retinoids in the embryo begin soon after conception and continue throughout the lifespan of all vertebrates. Both naturally occurring and synthetic retinoids are used in the therapy of various skin diseases, especially acne, for augmenting the treatment of diabetes, and as cancer chemopreventive agents. Retinol metabolites serve as ligands that activate specific transcription factors in the superfamily of steroid/retinoid/thyroid/vitamin D/orphan receptors and thereby control gene expression. Additionally, retinoids may also function through non-genomic actions. Various retinoid binding proteins serve as partners in retinoid function. These binding proteins show high specificity and affinity for specific retinoids and seem to control retinoid metabolism in vivo qualitatively and quantitatively by reducing 'free' retinoid concentrations, protecting retinoids from non-specific interactions, and chaperoning access of metabolic enzymes to retinoids. Implementation of the physiological effects of retinoids depends on the spatial-temporal expressions of binding proteins, receptors and metabolic enzymes. This review will discuss current understanding of the enzymes that catalyze retinol and retinoic acid metabolism and their unique and integral relationship to retinoid binding proteins.