RESUMEN
In India, natural preparations derived from the plants are widely use for the treatments of various diseases. Hence, it becomes necessary to assess the modulating action of the plant extract when associated with other substances. Potassium canrenoate (PC) is a synthetic steroid and is used in the treatment of hypertension. It is not only a genotoxic agent, but also a tumor-initiating agent. In the present study, the effect of various doses (i.e., 5, 10, 20, and 30 µM) of PC were studied for their genotoxic effects in the presence of S9 mix in cultured human lymphocytes, using mitotic index, chromosomal aberrations, sister chromatid exchanges, and replication index as parameters. PC was found to be genotoxic at 20 and 30 µM. Treatment of 30 µM of PC was given along with different doses of Plumbago zeylanica extract (i.e., 107.5, 212.5, 315, and 417 µg/mL) of the culture medium. A dose-dependent decrease in the genotoxic effects of PC was observed. The result suggested that the plant extract per se does not have genotoxic potential, but can modulate the genotoxicity of PC in cultured human lymphocytes.
Asunto(s)
Ácido Canrenoico/toxicidad , Leucocitos Mononucleares/efectos de los fármacos , Mutágenos/toxicidad , Extractos Vegetales/farmacología , Plumbaginaceae/química , Ácido Canrenoico/antagonistas & inhibidores , Ciclo Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Aberraciones Cromosómicas/inducido químicamente , Aberraciones Cromosómicas/efectos de los fármacos , Interacciones Farmacológicas , Humanos , India , Extractos Vegetales/aislamiento & purificación , Intercambio de Cromátides Hermanas/efectos de los fármacosRESUMEN
In humans, corticosteroids are often administered prenatally to improve lung development in preterm neonates. Studies in exposed children as well as in children, whose mothers experienced significant stress during pregnancy indicate behavioral problems and possible increased occurrence of epileptic spasms. This study investigated whether prenatal corticosteroid exposure alters early postnatal seizure susceptibility and behaviors. On gestational day 15, pregnant rats were injected i.p. with hydrocortisone (2×10mg/kg), betamethasone (2×0.4mg/kg) or vehicle. On postnatal day (P)15, seizures were induced by flurothyl or kainic acid (3.5 or 5.0mg/kg). Horizontal bar holding was determined prior to seizures and again on P17. Performance in the elevated plus maze was assessed on P20-22. Prenatal exposure to betamethasone decreased postnatal susceptibility to flurothyl-induced clonic seizures but not to kainic acid-induced seizures. Prenatal hydrocortisone decreased postnatal weight but did not affect seizure susceptibility. Hydrocortisone alone did not affect performance in behavioral tests except for improving horizontal bar holding on P17. A combination of prenatal hydrocortisone and postnatal seizures resulted in increased anxiety. Prenatal exposure to mineralocorticoid receptor blocker canrenoic acid did not attenuate, but surprisingly amplified the effects of hydrocortisone on body weight and significantly worsened horizontal bar performance. Thus, prenatal exposure to excess corticosteroids alters postnatal seizure susceptibility and behaviors. Specific effects may depend on corticosteroid species.
Asunto(s)
Ansiedad/inducido químicamente , Betametasona/toxicidad , Conducta Exploratoria/efectos de los fármacos , Hidrocortisona/toxicidad , Efectos Tardíos de la Exposición Prenatal , Desempeño Psicomotor/efectos de los fármacos , Convulsiones/inducido químicamente , Animales , Betametasona/administración & dosificación , Ácido Canrenoico/farmacología , Ácido Canrenoico/toxicidad , Convulsivantes/toxicidad , Susceptibilidad a Enfermedades/inducido químicamente , Femenino , Flurotilo/toxicidad , Hidrocortisona/administración & dosificación , Ácido Kaínico/toxicidad , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Antagonistas de Receptores de Mineralocorticoides , Embarazo , Ratas , Ratas Sprague-Dawley , Receptores de Mineralocorticoides/fisiología , Estado Epiléptico/inducido químicamente , Aumento de Peso/efectos de los fármacosRESUMEN
Potassium canrenoate (PC), a competitive aldosterone antagonist previously found to increase tumor incidence in rats and to produce genotoxic effects in in vitro systems, was examined in rats to acquire information on its genotoxic activity in vivo. Intragastric administration of 1/2 LD50 produced, as revealed by the Comet assay, a modest but statistically significant increase in the frequency of DNA lesions in liver but not in thyroid and bone marrow of male rats, and in thyroid and bone marrow but not in liver of female rats. In contrast with the frankly positive responses observed in primary cultures of rat hepatocytes (Martelli et al., Mutagenesis 14 (1999) 463-472) any evidence of DNA repair and micronuclei formation was absent in liver of rats treated with 1/2 LD50, and initiation of enzyme-altered liver preneoplastic lesions did not occur in the liver of rats given 100 mg/kg PC once a week for 6 successive weeks. A high and dose-dependent frequency of DNA lesions was found to occur in testes and ovaries of rats given single doses ranging from 1/8 to 1/2 LD50.
Asunto(s)
Ácido Canrenoico/toxicidad , Daño del ADN , Antagonistas de Receptores de Mineralocorticoides/toxicidad , Animales , Médula Ósea/efectos de los fármacos , Ensayo Cometa , Fragmentación del ADN , Reparación del ADN , Relación Dosis-Respuesta a Droga , Eritrocitos/efectos de los fármacos , Femenino , Hepatocitos/efectos de los fármacos , Hígado/efectos de los fármacos , Masculino , Pruebas de Micronúcleos , Ovario/efectos de los fármacos , Ratas , Testículo/efectos de los fármacos , Glándula Tiroides/efectos de los fármacosRESUMEN
Potassium canrenoate (PC), a competitive aldosterone antagonist used as a diuretic and in the treatment of hypertension, was examined for its capacity to produce genotoxic effects in cultured rat and human cells. At subtoxic concentrations (10-90 microM) PC was found to induce a dose-dependent degree of DNA fragmentation, as detected by the Comet assay, and of DNA repair synthesis, as measured by quantitative autoradiography, in primary cultures of hepatocytes from rat and human donors of both genders. In rat hepatocytes both DNA fragmentation and DNA repair were more marked after 3 h than after 20 h exposure and in cultures from females than from males. In human hepatocytes from one male and two female donors, PC caused a similar effect in terms of DNA fragmentation, whereas DNA repair was detected in cultures from only two of the same three donors and was less marked than in rat hepatocytes. A modest but statistically significant increase in micronucleated cells was present in primary cultures of replicating rat hepatocytes exposed to 10 or 30 microM PC for 48 h, the response being, in this case also, more evident in females than in males. In contrast, PC did not induce micronucleus formation in human hepatocytes from two female donors. Any evidence of DNA fragmentation and micronucleus formation was absent in cultured human lymphocytes. Taken as a whole these findings support the hypothesis that hepatocytes activate PC to DNA-damaging reactive species. PC induced the observed genotoxic effects at concentrations close to those produced in humans by the administration of therapeutic doses, but these effects were as a whole more marked in rat than in human hepatocytes. Since PC shares the 17-hydroxy-3-oxopregna-4,6-diene structure with cyproterone acetate, chlormadinone acetate and megestrol acetate, previously found to be genotoxic to both rat and human hepatocytes, the potential carcinogenic hazard of this type of steroids cannot be neglected.
Asunto(s)
Ácido Canrenoico/toxicidad , Antagonistas de Receptores de Mineralocorticoides/toxicidad , Adulto , Anciano , Animales , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , ADN/biosíntesis , ADN/efectos de los fármacos , Daño del ADN , Fragmentación del ADN/efectos de los fármacos , Reparación del ADN , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Hígado/citología , Hígado/efectos de los fármacos , Hígado/metabolismo , Linfocitos/citología , Linfocitos/efectos de los fármacos , Linfocitos/metabolismo , Masculino , Pruebas de Micronúcleos , Pruebas de Mutagenicidad , Ratas , Ratas Sprague-DawleyRESUMEN
Potassium canrenoate (PC) is a diuretic with antialdosterone action, reducing the reabsorption of sodium in the efferent renal tubules. This drug has been reported to damage only the marginal cells of the stria vascularis in the cochlea. The perilymphatic space of the guinea pig cochlea was perfused with an artificial perilymph containing 5 x 10(-3) M potassium canrenoate. Following the onset of perfusion, the endocochlear dc potential (EP) gradually declined to around 10 mV but did not become negative even when the perfusion was continued. A similar decrease in EP was observed in kanamycin-deafened guinea pigs. When the respirator was turned off and perfusion discontinued, a large negative EP appeared during 5 min of anoxia in normal guinea pigs but not in the kanamycin-deafened guinea pigs. The decreased EP recovered to preanoxic level after resumption of ventilation. The cochlear microphonics (CM) also gradually declined in parallel with the EP. The summating potential (SP) showed only a minor change. The potassium ion activity in the endolymph decreased slightly but the sodium ion activity remained unchanged during perfusion. These findings suggest that the main target of the PC is the cells of the stria vascularis.