RESUMO
alpha-Solanine and alpha-chaconine are two naturally occurring steroidal glycoalkaloids in potatoes (Solanum tuberosum), and solanidine-N-oxide is a corresponding steroidal aglycone. The objective of this research was to screen potential cyto-toxicity of these potato glycoalkaloids using bovine oocyte maturation, in vitro fertilization techniques and subsequent embryonic development as the in vitro model. A randomized complete block design with four in vitro oocyte maturation (IVM) treatments (Experiment 1) and four in vitro embryo culture (IVC) treatments (Experiment 2) was used. In Experiment 1, bovine oocytes (n=2506) were matured in vitro in medium supplemented with 6 microM of alpha-solanine, alpha-chaconine, solanidine-N-oxide or IVM medium only. The in vitro matured oocytes were then subject to routine IVF and IVC procedures. Results indicated that exposure of bovine oocytes to the steroidal glycoalkaloids during in vitro maturation inhibited subsequent pre-implantation embryo development. Potency of the embryo-toxicity varied between these steroidal glycoalkaloids. In Experiment 2, IVM/IVF derived bovine embryos (n=2370) were cultured in vitro in medium supplemented with 6 microM of alpha-solanine, alpha-chaconine, solanidine-N-oxide or IVC medium only. The results showed that the pre-implantation embryo development is inhibited by exposure to these glycoalkaloids. This effect is significant during the later pre-implantation embryo development period as indicated by fewer numbers of expanded and hatched blastocysts produced in the media containing these alkaloids. Therefore, we conclude that in vitro exposure of oocytes and fertilized ova to the steroidal glycoalkaloids from potatoes inhibits pre-implantation embryo development. Furthermore, we suggest that ingestion of Solanum species containing toxic amounts of glycoalkaloids may have negative effects on pre-implantation embryonic survival.
Assuntos
Bovinos/embriologia , Desenvolvimento Embrionário/efeitos dos fármacos , Solanina/análogos & derivados , Solanina/farmacologia , Solanum tuberosum/química , Animais , Diosgenina , Fertilização in vitro/veterinária , Alcaloides de Solanáceas/farmacologia , Técnicas de Cultura de TecidosRESUMO
During endochondral ossification, two secreted signals, Indian hedgehog (Ihh) and parathyroid hormone-related protein (PTHrP), have been shown to form a negative feedback loop regulating the onset of hypertrophic differentiation of chondrocytes. Bone morphogenetic proteins (BMPs), another family of secreted factors regulating bone formation, have been implicated as potential interactors of the Ihh/PTHrP feedback loop. To analyze the relationship between the two signaling pathways, we used an organ culture system for limb explants of mouse and chick embryos. We manipulated chondrocyte differentiation by supplementing these cultures either with BMP2, PTHrP and Sonic hedgehog as activators or with Noggin and cyclopamine as inhibitors of the BMP and Ihh/PTHrP signaling systems. Overexpression of Ihh in the cartilage elements of transgenic mice results in an upregulation of PTHrP expression and a delayed onset of hypertrophic differentiation. Noggin treatment of limbs from these mice did not antagonize the effects of Ihh overexpression. Conversely, the promotion of chondrocyte maturation induced by cyclopamine, which blocks Ihh signaling, could not be rescued with BMP2. Thus BMP signaling does not act as a secondary signal of Ihh to induce PTHrP expression or to delay the onset of hypertrophic differentiation. Similar results were obtained using cultures of chick limbs. We further investigated the role of BMP signaling in regulating proliferation and hypertrophic differentiation of chondrocytes and identified three functions of BMP signaling in this process. First we found that maintaining a normal proliferation rate requires BMP and Ihh signaling acting in parallel. We further identified a role for BMP signaling in modulating the expression of IHH: Finally, the application of Noggin to mouse limb explants resulted in advanced differentiation of terminally hypertrophic cells, implicating BMP signaling in delaying the process of hypertrophic differentiation itself. This role of BMP signaling is independent of the Ihh/PTHrP pathway.
Assuntos
Proteínas Morfogenéticas Ósseas/metabolismo , Condrócitos/citologia , Osteogênese/fisiologia , Hormônio Paratireóideo/metabolismo , Proteínas/metabolismo , Transativadores/metabolismo , Animais , Diferenciação Celular , Divisão Celular , Embrião de Galinha , Extremidades/embriologia , Retroalimentação , Proteínas Hedgehog , Hipertrofia , Camundongos , Camundongos Transgênicos , Modelos Biológicos , Técnicas de Cultura de Órgãos , Proteína Relacionada ao Hormônio Paratireóideo , Transdução de Sinais , Transativadores/genéticaRESUMO
Coordinated growth and differentiation of external genitalia generates a proximodistally elongated structure suitable for copulation and efficient fertilization. The differentiation of external genitalia incorporates a unique process, i.e. the formation of the urethral plate and the urethral tube. Despite significant progress in molecular embryology, few attempts have been made to elucidate the molecular developmental processes for external genitalia. The sonic hedgehog (Shh) gene and its signaling genes have been found to be dynamically expressed during murine external genitalia development. Functional analysis by organ culture revealed that Shh could regulate mesenchymally expressed genes, patched 1 (Ptch1), bone morphogenetic protein 4 (Bmp4), Hoxd13 and fibroblast growth factor 10 (Fgf10), in the anlage: the genital tubercle (GT). Activities of Shh for both GT outgrowth and differentiation were also demonstrated. Shh(-/-) mice displayed complete GT agenesis, which is compatible with such observations. Furthermore, the regulation of apoptosis during GT formation was revealed for the first time. Increased cell death and reduced cell proliferation of the Shh(-/-) mice GT were shown. A search for alterations of Shh downstream gene expression identified a dramatic shift of Bmp4 gene expression from the mesenchyme to the epithelium of the Shh mutant before GT outgrowth. Regulation of mesenchymal Fgf10 gene expression by the epithelial Shh was indicated during late GT development. These results suggest a dual mode of Shh function, first by the regulation of initiating GT outgrowth, and second, by subsequent GT differentiation.
Assuntos
Genitália/embriologia , Transdução de Sinais , Transativadores/metabolismo , Fatores de Transcrição , Animais , Apoptose/fisiologia , Proteína Morfogenética Óssea 4 , Proteínas Morfogenéticas Ósseas/genética , Diferenciação Celular , Divisão Celular , Indução Embrionária , Feminino , Fator 10 de Crescimento de Fibroblastos , Fatores de Crescimento de Fibroblastos/genética , Regulação da Expressão Gênica no Desenvolvimento , Proteínas Hedgehog , Proteínas de Homeodomínio/genética , Peptídeos e Proteínas de Sinalização Intracelular , Masculino , Proteínas de Membrana/genética , Mesoderma , Camundongos , Camundongos Knockout , Camundongos Mutantes , Mutação , Técnicas de Cultura de Órgãos , Receptores Patched , Receptor Patched-1 , Receptores de Superfície Celular , Transativadores/genéticaRESUMO
The aristaless-related homeobox genes Prx1 and Prx2 are required for correct skeletogenesis in many structures. Mice that lack both Prx1 and Prx2 functions display reduction or absence of skeletal elements in the skull, face, limbs and vertebral column. A striking phenotype is found in the lower jaw, which shows loss of midline structures, and the presence of a single, medially located incisor. We investigated development of the mandibular arch of Prx1(-/-)Prx2(-/-) mutants to obtain insight into the molecular basis of the lower jaw abnormalities. We observed in mutant embryos a local decrease in proliferation of mandibular arch mesenchyme in a medial area. Interestingly, in the oral epithelium adjacent to this mesenchyme, sonic hedgehog (Shh) expression was strongly reduced, indicative of a function for Prx genes in indirect regulation of SHH: Wild-type embryos that were exposed to the hedgehog-pathway inhibitor, jervine, partially phenocopied the lower jaw defects of Prx1(-/-)Prx2(-/-) mutants. In addition, this treatment led to loss of the mandibular incisors. We present a model that describes how loss of Shh expression in Prx1(-/-)Prx2(-/-) mutants leads to abnormal morphogenesis of the mandibular arch.
Assuntos
Região Branquial/embriologia , Proteínas de Homeodomínio/fisiologia , Mandíbula/embriologia , Transativadores/fisiologia , Animais , Região Branquial/citologia , Divisão Celular/fisiologia , Regulação para Baixo , Feminino , Genes Homeobox , Proteínas Hedgehog , Proteínas de Homeodomínio/genética , Incisivo/anormalidades , Incisivo/embriologia , Masculino , Mandíbula/anormalidades , Mesoderma , Camundongos , Camundongos Transgênicos , Morfogênese , Mutação , Gravidez , Dente/embriologia , Transativadores/genéticaRESUMO
In the caudal neural tube, oligodendrocyte progenitors (OLPs) originate in the ventral neuroepithelium under the influence of Sonic hedgehog (SHH), then migrate throughout the spinal cord and brainstem before differentiating into myelin-forming cells. We present evidence that oligodendrogenesis in the anterior neural tube follows a similar pattern. We show that OLPs in the embryonic mouse forebrain express platelet-derived growth factor alpha-receptors (PDGFRA), as they do in more caudal regions. They first appear within a region of anterior hypothalamic neuroepithelium that co-expresses mRNA encoding SHH, its receptor PTC1 (PTCH) and the transcription factors OLIG1, OLIG2 and SOX10. Pdgfra-positive progenitors later spread through the forebrain into areas where Shh is not expressed, including the cerebral cortex. Cyclopamine inhibited OLP development in cultures of mouse basal forebrain, suggesting that hedgehog (HH) signalling is obligatory for oligodendrogenesis in the ventral telencephalon. Moreover, Pdgfra-positive progenitors did not appear on schedule in the ventral forebrains of Nkx2.1 null mice, which lack the telencephalic domain of Shh expression. However, OLPs did develop in cultures of Nkx2.1(-/-) basal forebrain and this was blocked by cyclopamine. OLPs also developed in neocortical cultures, even though Shh transcripts could not be detected in the embryonic cortex. Here, too, the appearance of OLPs was suppressed by cyclopamine. In keeping with these findings, we detected mRNA encoding SHH and Indian hedgehog (IHH) in both Nkx2.1(-/-) basal forebrain cultures and neocortical cultures. Overall, the data are consistent with the idea that OLPs in the telencephalon, possibly even some of those in the cortex, develop under the influence of SHH in the ventral forebrain.
Assuntos
Oligodendroglia/citologia , Proteínas/metabolismo , Células-Tronco/citologia , Telencéfalo/citologia , Transativadores , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos , Diferenciação Celular , Linhagem da Célula , Células Cultivadas , Córtex Cerebral/metabolismo , Córtex Cerebral/patologia , Proteínas de Ligação a DNA/genética , Expressão Gênica , Homologia de Genes , Proteínas Hedgehog , Proteínas de Grupo de Alta Mobilidade/genética , Peptídeos e Proteínas de Sinalização Intracelular , Proteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas do Tecido Nervoso/genética , Fator de Transcrição 2 de Oligodendrócitos , Receptores Patched , Receptor Patched-1 , Prosencéfalo/metabolismo , Prosencéfalo/patologia , Proteínas/genética , Ratos , Ratos Sprague-Dawley , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/genética , Receptores de Superfície Celular , Fatores de Transcrição SOXE , Telencéfalo/metabolismo , Fatores de TranscriçãoRESUMO
Intrinsic or acquired resistance of tumor cells to multiple cytotoxic drugs (multidrug resistance MDR) is a major cause of failure of cancer chemotherapy. MDR is often caused by elevated expression of drug transporters such as P-glycoprotein (P-gp) or multidrug resistance protein (MRP). A number of compounds, termed chemosensitizers, have little or no cytotoxic action of their own, but inhibit (P-gp) or MRP-mediated drug export and are capable of sensitizing MDR cells to the cytotoxic effects of chemotherapeutic drugs. Here we examined the ability of steroidal alkaloids of plant origin, namely the Veratrum sp. alkaloid cyclopamine and the Lycopersicon sp. alkaloid tomatidine, to act as potent and effective chemosensitizers in multidrug resistant tumor cells. Drug uptake was determined by measuring accumulation of tetramethylrosamine in multidrug resistant NCI AdrR human adenocarcinoma cells. Resistance to adriamycin and vinblastine was determined by utilizing the MTT cell survival assay. Cyclopamine and tomatidine elevate tetramethylrosamine uptake by NCI AdrR cells and sensitize the cells to the cytotoxic action of adriamycin and vinblastine. In both cases these agents are comparable in patency and efficacy to verapamil, a reversal agent commonly used in MDR research. It is concluded that steroidal alkaloids of plant origin act as inhibitors of P-gp-mediated drug transport and multidrug resistance and therefore may serve as chemosensitizers in combination chemotherapy with conventional cytotoxic drugs for treating multidrug resistant cancer.
Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores , Antineoplásicos Fitogênicos/farmacologia , Tomatina/análogos & derivados , Tomatina/farmacologia , Alcaloides de Veratrum/farmacologia , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/metabolismo , Diosgenina , Doxorrubicina/farmacologia , Resistência a Múltiplos Medicamentos , Resistencia a Medicamentos Antineoplásicos , Compostos Heterocíclicos com 3 Anéis/metabolismo , Humanos , Estrutura Molecular , Rodaminas , Alcaloides de Solanáceas/química , Alcaloides de Solanáceas/metabolismo , Alcaloides de Solanáceas/farmacologia , Tomatina/química , Tomatina/metabolismo , Células Tumorais Cultivadas , Alcaloides de Veratrum/química , Alcaloides de Veratrum/metabolismo , Vimblastina/farmacologiaRESUMO
Cyclopamine is a teratogenic steroidal alkaloid that causes cyclopia by blocking Sonic hedgehog (Shh) signal transduction. We have tested whether this activity of cyclopamine is related to disruption of cellular cholesterol transport and putative secondary effects on the Shh receptor, Patched (Ptc). First, we report that the potent antagonism of Shh signaling by cyclopamine is not a general property of steroidal alkaloids with similar structure. The structural features of steroidal alkaloids previously associated with the induction of holoprosencephaly in whole animals are also associated with inhibition of Shh signaling in vitro. Second, by comparing the effects of cyclopamine on Shh signaling with those of compounds known to block cholesterol transport, we show that the action of cyclopamine cannot be explained by inhibition of intracellular cholesterol transport. However, compounds that block cholesterol transport by affecting the vesicular trafficking of the Niemann-Pick C1 protein (NPC1), which is structurally similar to Ptc, are weak Shh antagonists. Rather than supporting a direct link between cholesterol homeostasis and Shh signaling, our findings suggest that the functions of both NPC1 and Ptc involve a common vesicular transport pathway. Consistent with this model, we find that Ptc and NPC1 colocalize extensively in a vesicular compartment in cotransfected cells.
Assuntos
Proteínas de Transporte , Colesterol/metabolismo , Glicoproteínas de Membrana , Proteínas/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transativadores , Alcaloides de Veratrum/farmacologia , Androstenos/farmacologia , Animais , Transporte Biológico/efeitos dos fármacos , Células COS , Embrião de Galinha , Proteínas Hedgehog , Peptídeos e Proteínas de Sinalização Intracelular , Proteína C1 de Niemann-Pick , Proteínas Oncogênicas/metabolismo , Progesterona/farmacologia , Proteínas Recombinantes/metabolismo , TransfecçãoRESUMO
Numerous naturally-occurring and synthetic compounds that were discovered initially because of their toxic properties, were later shown to possess biological activities beneficial to humans that enabled them to serve as templates for the development of useful medicinal agents. A prominent example is thalidomide, a synthetic drug that gained notoriety originally due to its catastrophic teratogenicity in humans. The discovery of thalidomide's efficacy in treating several diseases has resulted in the recrudescence of the drug to society's usage. A current example of this phenomenon is the plant teratogen cyclopamine (11-deoxojervine), whose deleterious terata-inducing effects were restricted to grazing animals, but whose recently discovered inhibition of Sonic hedgehog signal transduction has provided both the potential to increase our understanding of organogenesis and to serve as a lead compound in drug development.
Assuntos
Proteínas/metabolismo , Teratogênicos/farmacologia , Talidomida/farmacologia , Transativadores , Alcaloides de Veratrum/farmacologia , Anormalidades Induzidas por Medicamentos/etiologia , Animais , Bioética , Proteínas Hedgehog , Humanos , Hipnóticos e Sedativos/química , Hipnóticos e Sedativos/farmacologia , Proteínas/efeitos dos fármacos , Proteínas/genética , Transdução de Sinais , Teratogênicos/química , Talidomida/química , Alcaloides de Veratrum/químicaRESUMO
Sonic hedgehog (Shh) is expressed in the posterior vertebrate limb bud mesenchyme and directs anteroposterior patterning and growth during limb development. Here we report an analysis of the pectoral fin phenotype of zebrafish sonic you mutants, which disrupt the shh gene. We show that Shh is required for the establishment of some aspects of anteroposterior polarity, while other aspects of anteroposterior polarity are established independently of Shh, and only later come to depend on Shh for their maintenance. We also demonstrate that Shh is required for the activation of posterior HoxD genes by retinoic acid. Finally, we show that Shh is required for normal development of the apical ectodermal fold, for growth of the fin bud, and for formation of the fin endoskeleton.
Assuntos
Padronização Corporal/fisiologia , Botões de Extremidades/crescimento & desenvolvimento , Proteínas/genética , Transativadores , Fator de Crescimento Transformador beta , Proteínas de Peixe-Zebra , Peixe-Zebra/embriologia , Animais , Proteína Morfogenética Óssea 2 , Proteínas Morfogenéticas Ósseas/genética , Divisão Celular/genética , Proteínas de Ligação a DNA/genética , Ectoderma , Embrião não Mamífero/citologia , Embrião não Mamífero/efeitos dos fármacos , Regulação da Expressão Gênica no Desenvolvimento , Proteínas Hedgehog , Proteínas Homeobox A10 , Proteínas de Homeodomínio/genética , Larva , Botões de Extremidades/citologia , Proteínas de Membrana/genética , Mutação , Receptores Patched , Proteínas/metabolismo , Receptores de Superfície Celular , Fatores de Transcrição/genética , Tretinoína/farmacologia , Alcaloides de Veratrum/farmacologiaRESUMO
The hair follicle is a source of epithelial stem cells and site of origin for several types of skin tumors. Although it is clear that follicles arise by way of a series of inductive tissue interactions, identification of the signaling molecules driving this process remains a major challenge in skin biology. In this study we report an obligatory role for the secreted morphogen Sonic hedgehog (Shh) during hair follicle development. Hair germs comprising epidermal placodes and associated dermal condensates were detected in both control and Shh -/- embryos, but progression through subsequent stages of follicle development was blocked in mutant skin. The expression of Gli1 and Ptc1 was reduced in Shh -/- dermal condensates and they failed to evolve into hair follicle papillae, suggesting that the adjacent mesenchyme is a critical target for placode-derived Shh. Despite the profound inhibition of hair follicle morphogenesis, late-stage follicle differentiation markers were detected in Shh -/- skin grafts, as well as cultured vibrissa explants treated with cyclopamine to block Shh signaling. Our findings reveal an essential role for Shh during hair follicle morphogenesis, where it is required for normal advancement beyond the hair germ stage of development.
Assuntos
Proteínas/fisiologia , Transplante de Pele/fisiologia , Pele/embriologia , Transativadores , Vibrissas/embriologia , Tecido Adiposo/embriologia , Animais , Indução Embrionária , Epiderme/embriologia , Proteínas Hedgehog , Camundongos , Camundongos Knockout , Camundongos Nus , Morfogênese , Técnicas de Cultura de Órgãos , Proteínas/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Glândulas Sebáceas/embriologia , Alcaloides de Veratrum/farmacologia , Vibrissas/efeitos dos fármacos , Vibrissas/transplanteRESUMO
The steroidal alkaloid cyclopamine produces cyclopia and holoprosencephaly when administered to gastrulation-stage amniote embryos. Cyclopamine-induced malformations in chick embryos are associated with interruption of Sonic hedgehog (Shh)-mediated dorsoventral patterning of the neural tube and somites. Cell types normally induced in the ventral neural tube by Shh are either absent or appear aberrantly at the ventral midline after cyclopamine treatment, while dorsal cell types normally repressed by Shh appear ventrally. Somites in cyclopamine-treated embryos show Pax7 expression throughout, indicating failure of sclerotome induction. Cyclopamine at concentrations of 20-100 nM blocks the response of neural plate explants to recombinant Shh-N in a dose-dependent manner. Similar concentrations have no effect on the post-translational modification of Shh by cholesterol in transfected COS-1 cells. Comparison of the effects of cyclopamine to those of the holoprosencephaly-inducing cholesterol synthesis inhibitor AY-9944 shows that cyclopamine does not induce malformations by interfering with cholesterol metabolism. Although AY-9944 does not interrupt Shh signaling in ovo, it blocks the response to Shh-N in explants cultured without an exogenous cholesterol source. As predicted by current models of the regulation of cholesterol metabolism, the response to Shh-N in AY-9944-treated explants is restored by providing exogenous cholesterol. However, exogenous cholesterol does not restore Shh signaling in cyclopamine-treated explants. These findings suggest that cyclopamine-induced teratogenesis is due to a more direct antagonism of Shh signal transduction.
Assuntos
Anti-Hipertensivos/farmacologia , Proteínas de Homeodomínio , Proteínas/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Teratogênicos/farmacologia , Transativadores , Alcaloides de Veratrum/farmacologia , Animais , Anticolesterolemiantes/farmacologia , Padronização Corporal , Células COS , Sistema Nervoso Central/embriologia , Embrião de Galinha , Colesterol/metabolismo , Proteínas Hedgehog , Proteínas Musculares/biossíntese , Proteínas do Tecido Nervoso/biossíntese , Fator de Transcrição PAX7 , Proteínas/genética , Transfecção , Dicloridrato de trans-1,4-Bis(2-clorobenzaminometil)ciclo-hexano/farmacologiaRESUMO
The potential induction of terata by solanidanes has been of public health concern since a report in 1972 hypothesized that certain birth defects in humans could be attributed to ingestion of blighted potatoes. The potential teratogenicity of solanidane alkaloids from potatoes and tomatoes in domestic livestock had been considered even earlier. In the present report, oral administration of the steroidal alkaloid glycosides alpha-solanine and alpha-chaconine and their aglycone solanidine is shown to induce craniofacial malformations (exencephaly, encephalocele, and anophthalmia) in Syrian hamsters. All three alkaloids, that were either isolated or obtained by hydrolysis from Solanum tuberosum (var. Kennebec) sprouts, possessed the 22-(R),25(S)-configuration in the indolizidine moiety with no other isomers present. Toxicity constraints precluded administration of dosages high enough to induce statistically significant levels of terata in litters dosed with alpha-chaconine and permitted the attainment of only marginal statistical significance for alpha-solanine. However, malformation induction at p < 0.005 was observed in litters upon dosing both the nontoxic aglycone solanidine and the derivative solanidine N-oxide at higher levels. The relatively high teratogenicity of nontoxic solanidine, compared to the glycosides, demonstrates that terata induction by solanidanes is not due to maternal toxicity nor is the oligosaccharide portion of steroidal alkaloid glycosides required to facilitate passage of the teratogen to the fetus. The teratogenicity of solanidine N-oxide, a putative metabolite, suggests that N-oxidation is not an effective mammalian detoxification pathway. Relative teratogenic potencies (RTP) were assigned to solanidanes by conversion of literature data to equimolar doses compared to the powerful Veratrum teratogen jervine and the nonteratogenic spirosolane tomatidine. RTP values are as follows: jervine (100), 22(S),-25(R)-solanidanes (50), alpha-chaconine (43), alpha-solanine (32), 22(R),25(S)-solanidine (32), solanidine N-oxide (32), 5 alpha,6-dihydrosolanidine (9), and tomatidine (0).
Assuntos
Benzo(a)pireno/metabolismo , Desenvolvimento Embrionário e Fetal/efeitos dos fármacos , Modelos Biológicos , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Alcaloides de Solanáceas/toxicidade , Solanum tuberosum/toxicidade , Teratogênicos/análise , Teratogênicos/toxicidade , Administração Oral , Animais , Cricetinae , Relação Dose-Resposta a Droga , Feminino , Cinética , Masculino , Mesocricetus , Gravidez , Efeitos Tardios da Exposição Pré-Natal , Alcaloides de Solanáceas/administração & dosagem , Especificidade da EspécieAssuntos
Anormalidades Induzidas por Medicamentos , Alcaloides de Solanáceas/química , Alcaloides de Veratrum/química , Animais , Cricetinae , Ossos Faciais/anormalidades , Feminino , Mesocricetus , Crânio/anormalidades , Alcaloides de Solanáceas/toxicidade , Relação Estrutura-Atividade , Alcaloides de Veratrum/toxicidadeAssuntos
Modelos Moleculares , Percepção de Profundidade , Humanos , Fotogrametria , EstereoisomerismoRESUMO
Comparison by GC analysis of purified alkaloid extracts of Solanum species revealed no measurable free solasodine, other spirosolanes, or any non-spirosolane steroidal alkaloid aglycones in unhydrolyzed total alkaloid fractions of fruit of Solanum elaeagnifolium Cav. (silverleaf nightshade), Solanum sarrachoides (S. villosum Lam.--hairy nightshade), Solanum dulcamara L. (European bittersweet nightshade) or Solanum melongena L. (eggplant). All alkaloidal material was apparently present as glycoside. Conversely, sprouts of Solanum tuberosum L. (potato) contained 67% of its alkaloids as glycosides, which was freed only upon hydrolysis with the remaining 33% present as free solanidine. GC/MS analysis of hydrolysates of purified extracts of the test Solanum species revealed that solasodine was a principal or sole aglycone of the alkaloid glycosides in each of the test species except Solanum tuberosum. In the latter, solanidine was the sole aglycone. Among the test species, exclusive of S. tuberosum, only S. dulcamara contained aglycones other than solasodine. In addition to solasodine, S. dulcamara contained appreciable amounts of an unknown spirosolane, an aglycone provisionally identified as soladulcidine. The induction of congenital craniofacial malformations in hamsters by high oral doses of the four Solanum species that contained mainly solasodine glycosides--S. elaeagnifolium, S. dulcamara, S. sarrachoides and S. melongena was compared to inductions of malformations by Solanum tuberosum, that contained mainly solanidane glycosides. Compared to controls, Solanum elaeagnifolium and Solanum dulcamara fruit both induced a high percentage incidence of deformed litters (20.4 and 16.3, respectively) that was statistically significant (P less than 0.001 level) while percentage incidence of deformed litters induced by Solanum sarrachoides and Solanum melongena fruit (9.5 and 7.6 respectively) were both higher than controls (3.4%), in neither case was the incidence statistically significant (P less than .05). Deformed litter incidence induced by sprouts of Solanum tuberosum was 24.0%, (P less than 0.001).
Assuntos
Disostose Craniofacial/induzido quimicamente , Glicosídeos/toxicidade , Plantas Tóxicas/análise , Alcaloides de Solanáceas/toxicidade , Tomatina/análogos & derivados , Animais , Disostose Craniofacial/patologia , Cricetinae , Feminino , Cromatografia Gasosa-Espectrometria de Massas , Glicosídeos/química , Gravidez , Alcaloides de Solanáceas/química , Solanum tuberosum/análise , Teratogênicos , Tomatina/química , Tomatina/toxicidadeRESUMO
Syrian hamsters were orally administered ground plant material from either Solanum sarrachoides, S. melongena, S. eleagnifolium, or S. dulcamara. Six of eight hamsters administered S. eleagnifolium and eight of 10 hamsters administered S. dulcamara died following administration of plant material and had gastric glandular mucosal necrosis and small intestinal mucosal necrosis with little inflammation. Hamsters administered S. sarrachoides or S. melongena did not die and had only lesions compatible with gastric distension. Both S. eleagnifolium and S. dulcamara contained solasodine glycoalkaloids(s), and S. dulcamara also contained an equal amount of other glycoalkaloids which were probably derived from soladulcidine (dihydrosolasodine). The lesions produced by these two plants were similar to those reported earlier to be caused by sprout material of S. tuberosum (in which solanidane alkaloids predominate) and by an alkaloid extract of S. tuberosum sprouts. Because of similarities in saponin-like activity and structure of solasodine glycoalkaloids to the solanidine glycoalkaloids of potato sprouts, the glycoalkaloids of S. dulcamara and S. eleagnifolium were probably the agents responsible for the lesions observed.
Assuntos
Mucosa Gástrica/efeitos dos fármacos , Mucosa Intestinal/efeitos dos fármacos , Plantas Tóxicas , Animais , Cricetinae , Mucosa Gástrica/patologia , Mucosa Intestinal/patologia , Mesocricetus , Necrose , Alcaloides de Solanáceas/toxicidadeRESUMO
Hamsters were gavaged either dried potato sprout material, alkaloid extract of potato sprouts, or the marc from which the alkaloid fraction was extracted and then were examined for gross and microscopic lesions. Nine of 10 hamsters receiving dried potato sprout material and 3 of 5 hamsters receiving alkaloid extract had severe gastric and intestinal mucosal necrosis which was most severe in the glandular stomach, duodenum and proximal jejunum. All control hamsters gavaged with water and all hamsters gavaged with the potato sprout marc survived to the time of euthanasia and did not have gross or microscopic lesions.
Assuntos
Alcaloides/toxicidade , Solanum tuberosum/toxicidade , Alcaloides/metabolismo , Animais , Cricetinae , Feminino , Mucosa Gástrica/patologia , Intestinos/patologia , Mesocricetus , Necrose , Extratos Vegetais/toxicidade , Solanina/toxicidadeRESUMO
Studies of teratogenic steroidal alkaloids from Veratrum and Solanum have shown that those bearing a basic nitrogen atom in ring F, shared or unshared with ring E, with bonding capabilities alpha to the steroid plane may be suspect as teratogens. Examples of steroidal alkaloids which produce terata but, until recently, have been of uncertain structure include muldamine and the isomeric 3, N-diformylsolasodines. The correlation of their structures with the structure-terata relationship developed by Keeler and Brown is discussed. A brief introduction to teratogenicity is presented.
Assuntos
Alcaloides de Solanáceas/toxicidade , Esteroides/toxicidade , Teratogênicos , Alcaloides de Veratrum/toxicidade , Conformação Molecular , Relação Estrutura-AtividadeRESUMO
The effects of the bladder carcinogens butyl(4-hydroxybutyl)nitrosamine (BBN) and butyl(3-carboxypropyl)-nitrosamine (BCPN) on proliferating transitional rat epithelium in organ culture were studied. At low to intermediate concentration ranges (0.5--2.9 mM), both compounds appeared to stimulate hyperplasia in some regions of epithelia. The major effect of both carcinogens, however, was to suppress hyperplasia in other regions of epithelia and, at higher concentrations (5--6 mM), to cause necrosis. For comparable concentrations, BBN was more effective in suppressing proliferation and causing necrosis than was BCPN.