RESUMEN
Coleus forskohlii root extract (CFE) represented by its bioactive constituent 'forskolin' is popularly used as a natural weight-lowering product, but the association of its use with liver-related risks is very limited. In the present study, the effect of standardized CFE with 10% forskolin on liver function of mice was examined. Mice were given 0-5% CFE in an AIN93G-based diet for 3-5 weeks. Food intake, body weights, relative organ weights and liver marker enzymes [aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP)] combined with histophatological analysis were assessed. CFE (0-0.5%) only had minimal effects on food intake and body weight whereas a significant difference was observed in mice receiving the highest dose (5% CFE). The extract 0.05-5% dose-dependently decreased visceral fat weight by between 16% and 63%, and a dose-dependent several folds increase was observed in liver weights and plasma AST, ALT and ALP activities with quick onset apparent after only 1 week of 0.5% CFE intake. The hepatic effect persisted throughout the 3-weeks course but was restored towards normalization within 1 week after withdrawal of treatment. Liver histology of mice fed 0.5% CFE for 3 weeks showed hepatocyte hypertrophy and fat deposition. In contrast, none of the hepatic responses measured were altered when mice were given a diet containing pure forskolin alone at the dose corresponding to its content in 0.5% CFE. The present study clearly indicated that forskolin was not involved in the CFE-induced hepatotoxicity and was caused by other unidentified constituents in CFE which warrants further studies.
Asunto(s)
Coleus/química , Hígado/efectos de los fármacos , Hígado/patología , Extractos Vegetales/efectos adversos , Alanina Transaminasa/sangre , Fosfatasa Alcalina/sangre , Animales , Aspartato Aminotransferasas/sangre , Biomarcadores/sangre , Peso Corporal , Colforsina/efectos adversos , Colforsina/toxicidad , Dieta , Relación Dosis-Respuesta a Droga , Hepatocitos/citología , Hepatocitos/efectos de los fármacos , Hepatocitos/metabolismo , Masculino , Ratones , Ratones Endogámicos ICR , Tamaño de los Órganos/efectos de los fármacos , Extractos Vegetales/administración & dosificación , Raíces de Plantas/químicaRESUMEN
OBJECTIVES: This study aimed to determine whether Coleus forskohlii extract (CFE) influences the anticoagulant action of warfarin in mice in vivo and its relationship with hepatic cytochrome P450 (CYP). METHODS: Mice were fed various doses of CFE standardised with 10% forskolin in a normal diet for one week, or in protein diets containing 7% and 20% casein (low and normal) for four weeks. They were then administered with warfarin by gavage on the last two days of the treatment regimen, and blood coagulation parameters, as well as hepatic CYP, were analysed at 18 h after the last dose. Direct interaction between CFE and forskolin with CYP2C was evaluated in vitro. KEY FINDINGS: CFE dose dependently increased hepatic total CYP content and S-warfarin 7-hydroxylase activity at a dietary level of ≥0.05%. Warfarin-induced anticoagulation was attenuated by CFE in parallel with CYP induction. The findings were similar in mice fed diets containing CFE and different ratios of protein. CFE directly inhibited CYP2C activity in mouse and human liver microsomes in vitro, whereas forskolin was only slightly inhibitory. CONCLUSIONS: CFE attenuates the anticoagulant action of warfarin by inducing hepatic CYP2C; thus, caution is required with the combination of warfarin and dietary supplements containing CFE.
Asunto(s)
Coleus/química , Colforsina/farmacología , Sistema Enzimático del Citocromo P-450/metabolismo , Interacciones de Hierba-Droga , Hígado/efectos de los fármacos , Extractos Vegetales/farmacología , Warfarina/metabolismo , Animales , Anticoagulantes/metabolismo , Anticoagulantes/farmacología , Caseínas/administración & dosificación , Dieta , Proteínas en la Dieta/administración & dosificación , Relación Dosis-Respuesta a Droga , Hígado/enzimología , Hígado/metabolismo , Masculino , Ratones , Ratones Endogámicos ICR , Microsomas Hepáticos/efectos de los fármacos , Warfarina/farmacologíaRESUMEN
When animals are infected with helminthic parasites, resistant hosts show type II helper T immune responses to expel worms. Recently, natural helper (NH) cells or nuocytes, newly identified type II innate lymphoid cells, are shown to express ST2 (IL-33 receptor) and produce IL-5 and IL-13 when stimulated with IL-33. Here we show the relevant roles of endogenous IL-33 for Strongyloides venezuelensis infection-induced lung eosinophilic inflammation by using Il33(-/-) mice. Alveolar epithelial type II cells (ATII) express IL-33 in their nucleus. Infection with S. venezuelensis or intranasal administration of chitin increases in the number of ATII cells and the level of IL-33. S. venezuelensis infection induces pulmonary accumulation of NH cells, which, after being stimulated with IL-33, proliferate and produce IL-5 and IL-13. Furthermore, S. venezuelensis infected Rag2(-/-) mice increase the number of ATII cells, NH cells, and eosinophils and the expression of IL-33 in their lungs. Finally, IL-33-stimulated NH cells induce lung eosinophilic inflammation and might aid to expel infected worms in the lungs.
Asunto(s)
Interleucinas/fisiología , Parasitosis Intestinales/complicaciones , Linfocitos/inmunología , Eosinofilia Pulmonar/etiología , Estrongiloidiasis/complicaciones , Animales , Líquido del Lavado Bronquioalveolar/citología , Linfocitos T CD4-Positivos/inmunología , Proteínas de Unión al ADN/deficiencia , Proteínas de Unión al ADN/genética , Interleucina-13/biosíntesis , Interleucina-33 , Interleucina-5/biosíntesis , Interleucinas/biosíntesis , Interleucinas/deficiencia , Interleucinas/genética , Parasitosis Intestinales/inmunología , Parasitosis Intestinales/patología , Larva , Linfocitos/efectos de los fármacos , Linfocitos/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Nippostrongylus/crecimiento & desarrollo , Nippostrongylus/inmunología , Alveolos Pulmonares/inmunología , Alveolos Pulmonares/patología , Eosinofilia Pulmonar/inmunología , Infecciones por Strongylida/complicaciones , Infecciones por Strongylida/inmunología , Infecciones por Strongylida/patología , Strongyloides/crecimiento & desarrollo , Strongyloides/inmunología , Estrongiloidiasis/inmunología , Estrongiloidiasis/patologíaRESUMEN
Ginkgo biloba extract (GBE) is a popular herbal ingredient used worldwide, but it is reported to induce bleeding as a serious adverse event. In this study we examined whether GBE induced spontaneous bleeding or accelerated warfarin anticoagulation via herb-drug interaction. Mice were given GBE or various active components of GBE orally for 5 days and blood coagulation parameters and hepatic cytochrome P450 enzymes (CYPs) were measured. Mice also received warfarin (racemate, (S)- or (R)-enantiomer) for the last 3 days of the 5-day regimen to examine GBE-warfarin interactions. Neither GBE (up to 1000 mg/kg) nor ginkgolide B (up to 140 mg/kg), a platelet-activating factor antagonist, influenced blood coagulation parameters. In contrast, GBE attenuated the anticoagulant action of warfarin. Bilobalide, a component of GBE that markedly induced hepatic CYPs including (S)-warfarin hydroxylase, showed similar effects. For (S)-warfarin, the anticoagulation action and the interaction with GBE was clear, while the influence on metabolism was greater for (R)-warfarin than for (S)-warfarin, which corresponded to the CYP types induced by GBE. These results suggest that GBE and ginkgolide B have no influence on blood coagulation in vivo, and that GBE attenuates the anticoagulation action of warfarin via induction of hepatic CYPs by bilobalide.
Asunto(s)
Anticoagulantes/efectos adversos , Ciclopentanos/farmacología , Sistema Enzimático del Citocromo P-450/química , Furanos/farmacología , Ginkgo biloba/química , Ginkgólidos/farmacología , Extractos Vegetales/farmacología , Warfarina/efectos adversos , Animales , Coagulación Sanguínea/efectos de los fármacos , Coagulantes/farmacología , Ciclopentanos/administración & dosificación , Sistema Enzimático del Citocromo P-450/efectos de los fármacos , Inducción Enzimática , Furanos/administración & dosificación , Ginkgólidos/administración & dosificación , Interacciones de Hierba-Droga , Lactonas/administración & dosificación , Lactonas/farmacología , Hígado/química , Hígado/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos ICR , Extractos Vegetales/administración & dosificación , Warfarina/administración & dosificaciónRESUMEN
Coleus forskohlii root extract (CFE) is popular for use as a weight loss dietary supplement. In this study, the influence of standardized CFE containing 10% active component forskolin on the hepatic drug metabolizing system was investigated to evaluate the safety through its drug interaction potential. Male ICR mice were fed AIN93G-based diets containing 0-5% CFE or 0.05% pure forskolin for 2-3 weeks. Intake of two different sources of 0.5% CFE significantly increased the relative liver weight, total content of hepatic cytochrome P450 (CYP) and induced CYPs (especially 2B, 2C, 3A types) and glutathione S-transferase (GST) activities. CFE significantly increased mRNA expression of CYPs and GST with dose related responses. However, unlike the CFE, intake of 0.05% pure forskolin was found to be associated with only weak induction in CYP3A and GST activities with no significant increases in relative liver weight, total hepatic content or other CYPs activities. The inductions of CYPs and GST by CFE were observed at 1 week of feeding and rapidly recovered by discontinuation of CFE. These results indicated the induction potential of CFE on CYPs, and that this effect was predominantly due to other, as yet unidentified constituents, and not forskolin contained in CFE.
Asunto(s)
Coleus/química , Sistema Enzimático del Citocromo P-450/biosíntesis , Microsomas Hepáticos/enzimología , Extractos Vegetales/farmacología , Animales , Secuencia de Bases , Cartilla de ADN , Inducción Enzimática , Glutatión Transferasa/metabolismo , Hígado/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos ICR , Tamaño de los Órganos/efectos de los fármacos , Raíces de Plantas/química , Reacción en Cadena en Tiempo Real de la PolimerasaRESUMEN
OBJECTIVES: Effects of repeated administration of Ginkgo biloba extract on pharmacokinetics and pharmacodynamics of tolbutamide were examined in rats fed a low-protein diet. METHODS: Rats were given a low (7% casein) or control (20% casein) protein diet for 21 days and administered Ginkgo biloba extract (100mg/kg per day) for the last 5 days. Tolbutamide was co-administered on the last day. Blood glucose and plasma tolbutamide concentrations were determined over the subsequent 12h and the activity of hepatic cytochrome P450s were determined at 12h after dosing. KEY FINDINGS: There were significant decreases in body weight, the ratio of liver to body weight, and plasma albumin concentrations in rats on the low-protein diet compared with controls. The hypoglycaemic effect of tolbutamide was significantly greater and the concentration of the drug in plasma was higher in the former group. The repeated administration of Ginkgo biloba extract had little influence on the hypoglycaemic effect of tolbutamide, but tended to decrease the drug concentration in plasma of control rats, while it reduced significantly the hypoglycaemic action and plasma concentration of tolbutamide in the protein-restricted rats. CONCLUSIONS: The effects of Ginkgo biloba extract on the pharmacokinetics and pharmacodynamics of tolbutamide were significantly enhanced in rats on the low-protein diet.
Asunto(s)
Peso Corporal/efectos de los fármacos , Dieta con Restricción de Proteínas , Ginkgo biloba , Interacciones de Hierba-Droga , Hipoglucemiantes/farmacología , Extractos Vegetales/farmacología , Tolbutamida/farmacología , Animales , Caseínas/administración & dosificación , Proteínas en la Dieta/administración & dosificación , Hipoglucemiantes/sangre , Hipoglucemiantes/farmacocinética , Hígado/efectos de los fármacos , Masculino , Tamaño de los Órganos/efectos de los fármacos , Ratas , Ratas Wistar , Albúmina Sérica/metabolismo , Tolbutamida/sangre , Tolbutamida/farmacocinéticaRESUMEN
AIMS: The current study aimed to investigate the effects of repeated treatment with nicotine on nicotinic and muscarinic receptors in the rat bladder. MAIN METHODS: Rats were administered nicotine (4.3 µmol/kg) subcutaneously (sc) twice a day for 10 days. The messenger RNA (mRNA) expression of nicotinic and muscarinic receptors in the bladder was examined by reverse transcription polymerase chain reaction (RT-PCR) and by a radioligand binding assay using [N-methyl-(3)H]scopolamine methyl chloride ([(3)H]NMS). The concentrations of nicotine and cotinine in plasma, tissues, and urine were estimated by ultra-performance liquid chromatography/electrospray ionization-mass spectrometry (UPLC/ESI-MS). KEY FINDINGS: mRNA of nicotinic receptor subunits (α1-α7, ß1-ß4, ε) and muscarinic receptor subtypes (M(1)-M(5)) was detected in the rat bladder. There was a significant increase in the mRNA expression of α3, ß1, ß2 and ß4 in the nicotine-treated rats (4.3 µmol/kg, s.c., b.i.d.) compared to the saline-treated group. Repeated administration of nicotine significantly increased the mRNA expression of the M(2) and M(3) muscarinic receptor subtypes in the rat bladder with a significant enhancement of [(3)H]NMS binding sites, compared to the saline-treated tissue. Nicotine was distributed at higher concentrations in the bladder than the heart and cerebral cortex. Furthermore, nicotine was excreted in rat urine at high concentrations. SIGNIFICANCE: The present study is the first to show that repeated treatment with nicotine affects pharmacologically-relevant nicotinic and muscarinic receptors in the bladder. Such changes may contribute to the etiology of lower urinary tract symptoms (LUTS) due to cigarette smoking.
Asunto(s)
Nicotina/efectos adversos , Nicotina/farmacocinética , ARN Mensajero/biosíntesis , Receptores Muscarínicos/biosíntesis , Receptores Nicotínicos/biosíntesis , Vejiga Urinaria/efectos de los fármacos , Animales , Sitios de Unión , Inyecciones Subcutáneas , Masculino , Nicotina/administración & dosificación , Unión Proteica , Ensayo de Unión Radioligante , Ratas , Ratas Sprague-Dawley , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Distribución Tisular , Regulación hacia Arriba , Vejiga Urinaria/metabolismoRESUMEN
We characterized contribution of N-oxide metabolites [1-methyl-4-piperidyl diphenylpropoxyacetate N-oxide (M-1) and 1-methyl-4-piperidyl benzilate N-oxide (M-2)] to the binding of muscarinic receptors in relation to the pharmacokinetics of propiverine in rats. The in vitro muscarinic receptor binding activity of M-2 was equipotent to that of propiverine, whereas M-1 was much less active. After the oral administration of propiverine (24.8-248 micromol/kg), there was relatively selective and longer-lasting binding of muscarinic receptors in the rat bladder compared with the submaxillary gland as shown by a significant increase in the apparent dissociation constant (K(d)) for specific binding of [N-methyl-(3)H]scopolamine ([(3)H]NMS). In addition, the intravesical instillation of M-2 produced a significant increase in K(d) for specific [(3)H]NMS binding in the rat bladder. Extremely high concentrations of M-1 and M-2 were detected in plasma after the oral administration of propiverine. The concentration of unbound M-2 was much higher than that of M-1 and propiverine in the rat plasma. The sum of maximal plasma unbound propiverine equivalents (C(max)) after the oral administration of propiverine at doses of 24.8, 74.3, and 248 micromol/kg was 66.0, 303, and 509 nM, respectively. The sum of corresponding area under the time-concentration curve from 0 to 12 h was 194, 2123, and 4645 nM . h, respectively. In fact, the unbound concentration of M-2 comprised more than 90% of sum of unbound propiverine equivalents in the plasma. After oral treatment with propiverine, the bladder showed the highest concentration of M-2, indicating specific distribution of this metabolite into the target organ. Thus, M-2 may contribute greatly to the relatively selective and long-lasting occupation of bladder muscarinic receptors after oral administration of propiverine.
Asunto(s)
Bencilatos/metabolismo , Bencilatos/farmacocinética , Receptores Muscarínicos/metabolismo , Vejiga Urinaria/metabolismo , Animales , Bencilatos/sangre , Antagonistas Colinérgicos/sangre , Antagonistas Colinérgicos/metabolismo , Antagonistas Colinérgicos/farmacocinética , Unión Proteica , Ratas , Glándula Submandibular/metabolismoRESUMEN
We have reviewed the binding of antimuscarinic agents, used to treat urinary dysfunction in patients with overactive bladder, to muscarinic receptors in target and non-target tissues in vivo. Transdermal administration of oxybutynin in rats led to significant binding in the bladder without long-term binding in the submaxillary gland and the abolishment of salivation evoked by oral oxybutynin. Oral solifenacin showed significant and long-lasting binding to muscarinic receptors in mouse tissues expressing the M(3) subtype. Oral tolterodine bound more selectively to muscarinic receptors in the bladder than in the submaxillary gland in mice. The muscarinic receptor binding activity of oral darifenacin in mice was shown to be pronounced and long-lasting in the bladder, submaxillary gland, and lung. In vivo quantitative autoradiography using (+)N-[(11)C]methyl-3-piperidyl benzilate in rats showed significant occupancy of brain muscarinic receptors on intravenous injection of oxybutynin, propiverine, solifenacin, and tolterodine. The estimated in vivo bladder selectivity compared to brain was significantly greater for solifenacin and tolterodine than oxybutynin. Darifenacin occupied few brain muscarinic receptors. Similar findings were also observed with positron emission tomography in conscious rhesus monkeys. The newer generation of antimuscarinic agents may be advantageous in the bladder selectivity after systemic administration.
Asunto(s)
Antagonistas Muscarínicos/uso terapéutico , Receptores Muscarínicos/efectos de los fármacos , Vejiga Urinaria Hiperactiva/tratamiento farmacológico , Animales , Autorradiografía/métodos , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Sistemas de Liberación de Medicamentos , Humanos , Macaca mulatta , Ratones , Antagonistas Muscarínicos/administración & dosificación , Antagonistas Muscarínicos/farmacología , Unión Proteica , Cintigrafía , Ratas , Receptores Muscarínicos/metabolismo , Vejiga Urinaria/metabolismo , Vejiga Urinaria/fisiopatología , Vejiga Urinaria Hiperactiva/fisiopatologíaRESUMEN
The present study was conducted to investigate the effects of repeated treatment with morphine on the drug's antinociceptive effects, intestinal absorption, and transepithelial transport. The antinociceptive effects of morphine in rats were markedly decreased after repeated oral administration of the drug for 5 d, indicating the development of tolerance. In the morphine-tolerant rats, intestinal absorption of morphine was determined using the in situ loop method. Absorption of morphine from the jejunum was significantly decreased after repeated administration. The permeability of human intestinal epithelial Caco-2 cells was increased in the efflux direction after repeated treatment. The repeated administration of morphine also reduced the cellular accumulation and efflux of P-glycoprotein substrates ([(3)H]vincristine and rhodamine123) from Caco-2 cells, suggesting that it enhances P-glycoprotein-mediated efflux in Caco-2 cells. These results suggest that repeated use enhances the efflux of morphine in the epithelial cells of the small intestine, subsequently decreasing its intestinal absorption.
Asunto(s)
Analgésicos Opioides/administración & dosificación , Movimiento Celular/efectos de los fármacos , Absorción Intestinal/efectos de los fármacos , Mucosa Intestinal/efectos de los fármacos , Mucosa Intestinal/metabolismo , Morfina/farmacocinética , Dimensión del Dolor/efectos de los fármacos , Animales , Células CACO-2 , Movimiento Celular/fisiología , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Humanos , Absorción Intestinal/fisiología , Mucosa Intestinal/citología , Intestino Delgado/citología , Intestino Delgado/efectos de los fármacos , Intestino Delgado/metabolismo , Masculino , Morfina/administración & dosificación , Dimensión del Dolor/métodos , Ratas , Ratas Sprague-DawleyRESUMEN
A single dose by gavage of bilobalide (30 mg/kg) was found to produce a time-dependent induction of hepatic cytochrome P450 (CYP) enzyme activity and protein expression in rats. An RT-PCR study further showed that mRNA expression of CYP2B was maximal at 6 h. Plasma and liver bilobalide concentration in rats following administration of Ginkgo biloba extract equivalent to bilobalide of approximately 40 mg/kg showed a similar response to that exhibited by mRNA expression. These findings suggest that bilobalide markedly induced hepatic CYPs, but the induction could be mitigated due to rapid elimination from the liver.
Asunto(s)
Ciclopentanos/farmacología , Sistema Enzimático del Citocromo P-450/efectos de los fármacos , Furanos/farmacología , Ginkgólidos/farmacología , Animales , Ciclopentanos/aislamiento & purificación , Ciclopentanos/farmacocinética , Sistema Enzimático del Citocromo P-450/metabolismo , Inducción Enzimática/efectos de los fármacos , Furanos/aislamiento & purificación , Furanos/farmacocinética , Regulación de la Expresión Génica/efectos de los fármacos , Ginkgo biloba/química , Ginkgólidos/aislamiento & purificación , Ginkgólidos/farmacocinética , Hígado/enzimología , Hígado/metabolismo , Masculino , Extractos Vegetales/farmacocinética , Extractos Vegetales/farmacología , ARN Mensajero/efectos de los fármacos , ARN Mensajero/metabolismo , Ratas , Ratas Wistar , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Factores de TiempoRESUMEN
We characterized muscarnic and purinergic receptors and urodynamic parameters in the bladder of cyclophosphamide (CYP)-treated rats to clarify the mechanisms involved in the pathophysiology of interstitial cystitis (IC). In the cystometry of CYP-treated rats compared with control rats, the micturition interval and micturition volume were significantly (55% and 77%, respectively) decreased and the frequency of micturition and basal pressure were significantly (3 and 2.3 times, respectively) increased. These changes in urodynamic parameters may characterize the detrusor overactivity occurring in CYP-treated rats. The maximal number of binding sites (B(max)) for specific binding of [N-methyl-(3)H]scopolamine methyl chloride ([(3)H]NMS) and alphabeta-methylene ATP [2,8-(3)H]tetrasodium salt ([(3)H]alphabeta-MeATP) was significantly (43% and 31%, respectively) decreased in the bladder of CYP-treated rats compared with control rats. On the other hand, the apparent dissociation constant (K(d)) for neither radioligand was significantly altered by the CYP treatment. K(i) value for the inhibition of bladder [(3)H]NMS binding by antimuscarinic agents (oxybutynin, tolterodine, darifenacin, and AF-DX 116) did not differ significantly between control and CYP-treated rats. The inhibition constant (K(i)) for the inhibition of bladder [(3)H]alphabeta-MeATP binding by purinergic antagonists (A-317491, PPADS) was significantly higher in CYP-treated rats than control rats. In conclusion, CYP treatment has been shown to cause down-regulation of pharmacologically relevant (muscarinic and purinergic) receptors in the bladder of rats. Thus, the present study offers further pharmacological evidence that both muscarinic and purinergic mechanisms contribute significantly to the urinary dysfunction due to IC.
Asunto(s)
Cistitis Intersticial/metabolismo , Cistitis Intersticial/fisiopatología , Receptores Muscarínicos/metabolismo , Receptores Purinérgicos/metabolismo , Vejiga Urinaria/fisiopatología , Urodinámica , Animales , Ciclofosfamida/toxicidad , Cistitis Intersticial/inducido químicamente , Femenino , Inmunosupresores/toxicidad , Ratas , Ratas Sprague-Dawley , Vejiga Urinaria/efectos de los fármacosRESUMEN
We examined the protective effect of dietary folate on benzene-induced chromosomal damage in bone marrow of mice regarding folate levels in diet and tissue. Male mice were fed either a deficient, basal, or high folate diet (0, 2, or 8 mg/kg diet, respectively) for 4 wk followed by a single dose of benzene. Plasma folate levels corresponded to those of dietary intake. Meanwhile, bone marrow, erythrocyte, and liver folate were decreased to 40% in the deficient group and almost saturated in the high group. Plasma homocysteine levels negatively correlated to levels of tissue folate. Chromosomal damage, evaluated by micronucleus assay, was not affected by folate status alone but was markedly enhanced by benzene, particularly in the deficient group (P < 0.05 vs. the basal and high groups). The activities of hepatic drug-metabolizing enzymes did not enhance benzene metabolism in the deficient groups, indicating that enhanced chromosomal damage was solely due to the low folate status. These results suggest that a low folate status can increase the risk of benzene-induced chromosomal damage in bone marrow, but excess folate intake does not enhance protection, as it is saturated in tissue.
Asunto(s)
Células de la Médula Ósea/efectos de los fármacos , Aberraciones Cromosómicas/efectos de los fármacos , Deficiencia de Ácido Fólico/fisiopatología , Ácido Fólico/administración & dosificación , Complejo Vitamínico B/administración & dosificación , Administración Oral , Animales , Benceno/toxicidad , Células de la Médula Ósea/citología , Daño del ADN/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Eritrocitos/química , Eritrocitos/metabolismo , Ácido Fólico/metabolismo , Deficiencia de Ácido Fólico/tratamiento farmacológico , Deficiencia de Ácido Fólico/metabolismo , Homocisteína/sangre , Hígado/química , Hígado/enzimología , Hígado/metabolismo , Masculino , Ratones , Pruebas de Micronúcleos , Distribución Aleatoria , Complejo Vitamínico B/metabolismoRESUMEN
In a search for substances related to the marked induction of hepatic cytochrome P450 (CYP) by ginkgo biloba extract (GBE), mice were given either GBE (1000 mg kg(-1)) or fractions of GBE for 5 days. The content and activity of CYPs were induced markedly by a bilobalide-rich fraction, but not by flavonoid-rich fractions. The level of induction by the bilobalide-rich fraction was almost the same as that induced by the unfractionated GBE, suggesting that bilobalide is largely responsible for the CYPs induction. To confirm these findings, mice were given various doses of bilobalide (10.5, 21 and 42 mg kg(-1)), or GBE (1000 mg kg(-1), containing bilobalide at 42 mg kg(-1)). Treatment with bilobalide induced CYPs markedly and in a dose-dependent manner, and the level of induction was quite similar between bilobalide (42 mg kg(-1)) and GBE. Treatment with GBE and with bilobalide greatly induced pentoxyresorufin O-dealkylase activity. These findings indicate that bilobalide is the major substance in GBE that induces hepatic CYPs.
Asunto(s)
Ciclopentanos/farmacología , Sistema Enzimático del Citocromo P-450/biosíntesis , Furanos/farmacología , Ginkgo biloba , Ginkgólidos/farmacología , Microsomas Hepáticos/efectos de los fármacos , Animales , Ciclopentanos/administración & dosificación , Relación Dosis-Respuesta a Droga , Inducción Enzimática , Furanos/administración & dosificación , Ginkgólidos/administración & dosificación , Técnicas In Vitro , Masculino , Ratones , Ratones Endogámicos ICR , Microsomas Hepáticos/enzimología , Extractos Vegetales/química , Extractos Vegetales/farmacologíaRESUMEN
BACKGROUND: Clinical trials have reported the cholesterol-lowering effects of soy protein intake, but the components responsible are not known. OBJECTIVE: This meta-analysis was primarily conducted to evaluate the precise effects of soy isoflavones on lipid profiles. The effects of soy protein that contains enriched and depleted isoflavones were also examined. DESIGN: PUBMED was searched for English-language reports of randomized controlled trials published from 1990 to 2006 that described the effects of soy protein intake in humans. Eleven studies were selected for the meta-analysis. RESULTS: Soy isoflavones significantly decreased serum total cholesterol by 0.10 mmol/L (3.9 mg/dL or 1.77%; P = 0.02) and LDL cholesterol by 0.13 mmol/L (5.0 mg/dL or 3.58%; P < 0.0001); no significant changes in HDL cholesterol and triacylglycerol were found. Isoflavone-depleted soy protein significantly decreased LDL cholesterol by 0.10 mmol/L (3.9 mg/dL or 2.77%; P = 0.03). Soy protein that contained enriched isoflavones significantly decreased LDL cholesterol by 0.18 mmol/L (7.0 mg/dL or 4.98%; P < 0.0001) and significantly increased HDL cholesterol by 0.04 mmol/L (1.6 mg/dL or 3.00%; P = 0.05). The reductions in LDL cholesterol were larger in the hypercholesterolemic subcategory than in the normocholesterolemic subcategory, but no significant linear correlations were observed between reductions and the starting values. No significant linear correlations were found between reductions in LDL cholesterol and soy protein ingestion or isoflavone intakes. CONCLUSIONS: Soy isoflavones significantly reduced serum total and LDL cholesterol but did not change HDL cholesterol and triacylglycerol. Soy protein that contained enriched or depleted isoflavones also significantly improved lipid profiles. Reductions in LDL cholesterol were larger in hypercholesterolemic than in normocholesterolemic subjects.