RESUMEN
Few pharmaceutical studies, with the exception of those on rectal solutions, are described on short chain fatty acid (SCFA) formulations-especially for sodium butyrate, which is a colonocyte preferential substrate. Highly dosed butyrate pellets (90%) were prepared and their coating was designed for colonic delivery. In vivo determination (pH and transit time of pellets in rats) allowed to respectively choose the grade and thickness (resistance of 6 h) of the pH-dependent coating (Eudragi L+S, 1:1). The coated pellets were administered to naturally butyrate-deprived rats. The rats' colonic mucosa had the particularity to weakly express mitochondrial HMG-CoA synthase, an enzyme that responds to luminal butyrate. The results did not show early absorption of butyrate, but a probable cecal loss in the rat cecum as cecal residence time of the pellets was important and as pH was propitious for the coating hydrolysis. It seemed that butyrate, given daily for 7 days without the other main SCFA. was unable to induce the enzyme and/or that the dose (0.32 mmol/day) was insufficient.
Asunto(s)
Ácido Butírico/administración & dosificación , Colon/metabolismo , Ácidos Polimetacrílicos , Administración Oral , Animales , Ácido Butírico/farmacocinética , Carmín/farmacocinética , Ciego/química , Coenzima A Ligasas/metabolismo , Colon/citología , Colon/enzimología , Colorantes , Mucosa Gástrica/química , Mucosa Gástrica/enzimología , Contenido Digestivo/química , Tránsito Gastrointestinal , Concentración de Iones de Hidrógeno , Hidroximetilglutaril-CoA Sintasa , Técnicas In Vitro , Norepinefrina/farmacocinética , Ratas , Ratas Endogámicas F344 , ComprimidosRESUMEN
Purpurin (1,2,4-trihydroxy-9,10-anthraquinone) is a natural pigment isolated from madder root (Rubia tinctorum) which inhibits the mutagenicity of a number of heterocyclic amines in the Ames mutagenicity test. Two effects were observed in the presence of purpurin. The rate of degradation of 3-hydroxyamino-1-methyl-5H-pyrido¿4,3-bindole ¿Trp-P-2(NHOH) at neutral pH was increased. The major product of this purpurin-dependent degradation was identified as the parent amine 3-amino-1-methyl-5H-pyrido¿4,3-bindole (Trp-P-2). Secondly, the rate of Trp-P-2 N-hydroxylation, the major route of bioactivation, by PCB-treated rat hepatic microsomes was markedly decreased. Cytochrome P450-dependent O-dealkylation of methoxy-, ethoxy- and pentoxyresorufin by these microsomes was also significantly inhibited by purpurin. The nature of this inhibition was competitive. Spectrophotometric investigations suggest no direct interaction between Trp-P-2 and purpurin. Furthermore, no evidence for Trp-P-2 binding was observed with carminic acid, a structural analog of purpurin, when it was immobilized on omega-aminohexyl agarose. Therefore, in vitro the proposed mechanism by which purpurin protects against heterocyclic amine-induced mutagenesis involves competitive inhibition of cytochrome P450-dependent bioactivation and accelerated degradation of the N-hydroxylamine to the parent amine.
Asunto(s)
Antraquinonas/farmacología , Antimutagênicos/farmacología , Carbolinas/farmacología , Microsomas Hepáticos/metabolismo , Mutágenos/farmacología , Salmonella typhimurium/efectos de los fármacos , Animales , Biodegradación Ambiental , Biotransformación , Carbolinas/farmacocinética , Carmín/análogos & derivados , Carmín/farmacocinética , Carmín/farmacología , Colorantes/farmacología , Cinética , Masculino , Microsomas Hepáticos/efectos de los fármacos , Pruebas de Mutagenicidad , Raíces de Plantas , RatasRESUMEN
The hepatic sinusoids are preferentially supplied with portal venous blood and equipped with fenestrated endothelial cells that are distinct from capillary endothelial cells. We previously observed in rats that sinusoidal capillarization proceeded concurrently with arterial blood supply during hepatocarcinogenesis. This study aimed to clarify the inducing role of arterialization in sinusoidal capillarization by investigating phenotypical, morphological and functional alterations to sinusoidal endothelial cells (SECs) in arterialized rat livers induced by portal branch ligation. At one week, after massive hepatic necrosis following ligation, the livers were restored to their normal architecture without causing post-necrotic fibrosis. At 12-21 weeks, they exhibited a normal histology except for mild pericellular fibrosis which developed along sinusoids or between adjacent hepatocytes. SECs expressed factor VIII-related antigen and showed a decrease in the number of fenestrae and porosity, still lacking any basement membrane but further retaining the functional capacity for carmine dye uptake. Stellate cells, while occasionally associated with large amounts of collagen bundles, contained many lipid droplets and expressed no alpha-smooth muscle actin, indicating a quiescent property. Kupffer cells were commonly found within the sinusoids. The present results indicate that arterialization of the liver induces a partial (but not complete) transition of SECs into capillary-type endothelial cells, suggesting that arterialization might be one of the factors which induce sinusoidal capillarization in the development of hepatocellular carcinoma.
Asunto(s)
Hígado/irrigación sanguínea , Hígado/patología , Sistema Porta/fisiología , Animales , Carmín/farmacocinética , Colorantes/farmacocinética , Endotelio/metabolismo , Endotelio/patología , Endotelio/ultraestructura , Macrófagos del Hígado/metabolismo , Macrófagos del Hígado/ultraestructura , Ligadura , Masculino , Microcirculación/fisiología , Microscopía Electrónica , Microscopía Electrónica de Rastreo , Fenotipo , Vena Porta , Ratas , Ratas Wistar , Organismos Libres de Patógenos EspecíficosRESUMEN
Carminic acid (CAR) enhances the antiviral activity of poly r(A-U) twelve-fold without increasing interferon induction, inactivating the vesicular stomatitis virus or inducing host cell cytotoxicity. Phase contrast photomicrographs of human foreskin fibroblasts (HSF) incubated with CAR alone, poly r(A-U) alone or with a CAR/poly r(A-U) combination illustrate that the CAR/poly r(A-U) combinations display altered subcellular distribution with the CAR being localized in the nucleoli and chromatin. Phase contrast and fluorescence photomicrographs of adriamycin (ADR)-treated and ADR/poly r(A-U)-treated HSF cells corroborate these findings. These results suggest that modulation of one or more nucleolar processes may be responsible for the enhanced antiviral activity.