RESUMEN
Ondine syndrome is the central congenital hypoventilation syndrome (CCHS) caused by the mutation of the PHOX2B gene. In late onset cases, the symptomatology often appears after an acute event (infection, general anesthesia, drug intake), increasing hypoventilation. We report a case of late onset Ondine curse in a 9-year-old girl. The diagnosis was made based on a hypercapnic coma complicating a respiratory infection caused by Mycoplasma pneumoniae and was confirmed by genetic testing. In the patient's history we found symptoms that had not been noted (e.g., enuresis, morning headache, adynamia), attesting to chronic hypoventilation. Through this observation, we review the literature on CCHS, notably late onset cases, which are rare and insidious, emphasizing the pre-existing hypoventilation symptoms in this child. This case underlines the need for all practitioners not to trivialize these symptoms so as to decrease the current delay in diagnosis for late onset CCHS and to introduce optimal care as soon as possible.
Asunto(s)
Diagnóstico Tardío , Apnea Central del Sueño/diagnóstico , Emparejamiento Base/genética , Niño , Análisis Mutacional de ADN , Diagnóstico Diferencial , Exones/genética , Femenino , Tamización de Portadores Genéticos , Pruebas Genéticas , Genotipo , Proteínas de Homeodominio/genética , Humanos , Hipercapnia/diagnóstico , Hipercapnia/terapia , Neumonía por Mycoplasma/complicaciones , Neumonía por Mycoplasma/diagnóstico , Neumonía por Mycoplasma/terapia , Polisomnografía , Respiración Artificial , Resucitación , Choque Cardiogénico/diagnóstico , Choque Cardiogénico/terapia , Apnea Central del Sueño/genética , Apnea Central del Sueño/terapia , Factores de Transcripción/genéticaRESUMEN
Necrotizing Staphylococcus aureus Panton-Valentine leukocidin (SA-PLV+) accounts for less than 1% of community-acquired lung diseases in children and young adults. Neonatal cases are exceptional. We report the observations of two newborn female twins, who were not breastfed, presenting a necrotizing lung disease due to the same strain of SA-PVL+ despite nasal decolonization measures taken. These two cases are informative and bring to light (1) the possibility of severe SA-PVL+ lung infections in young infants and (2) their strictly intrafamilial mode of transmission for which eradication measures were ineffective.
Asunto(s)
Toxinas Bacterianas/metabolismo , Exotoxinas/metabolismo , Leucocidinas/metabolismo , Neumonía Estafilocócica/microbiología , Neumonía Estafilocócica/transmisión , Staphylococcus aureus/metabolismo , Adulto , Antibacterianos/uso terapéutico , Infecciones Comunitarias Adquiridas/prevención & control , Familia , Femenino , Humanos , Recién Nacido , Pruebas de Sensibilidad Microbiana , Necrosis , Neumonía Estafilocócica/diagnóstico por imagen , Neumonía Estafilocócica/tratamiento farmacológico , Neumonía Estafilocócica/patología , Radiografía , Staphylococcus aureus/patogenicidad , Resultado del Tratamiento , Gemelos MonocigóticosRESUMEN
In asthmatic children, control of the disease is perfect when no symptoms occur and lung function is normal. The aim of this study is to analyse the role of plethysmography in the follow-up of asthmatic children. We present the results of a retrospective study of lung function (plethysmography and forced expiratory flow) in about 100 asthmatic children aged five to 16years. FEV1/FVC less than 80% predicted was considered as pathological (airflow obstruction). The ratio RV/TLC was considered pathological if greater than 30% and RV was considered pathological if greater than 120% (lung hyperinflation). Bronchodilator reversibility was performed in all patients. All patients were studied in a stable condition. None had developed any asthmatic exacerbations during the past month. We found a significant correlation between the residual volume/total lung capacity (RV/TLC) ratio and, on one hand: FEV1 (p<0.0001, R=-0.374), and on the other hand FEV1/FVC (p=0.07, R=-0.182) or forced expiratory flow 25-75 (p=0.03, R=-0.216). When comparing children with (n=40) and without (n=60) lung hyperinflation, we noticed more diurnal symptoms (30/40 vs 10/60, p=0.05), lower weight (33.9kg vs 41.8kg, p<0.05) and lower body mass index (16.9kg/m(2) vs 18.4kg/m(2), p<0.01). Among the children with defined airway obstruction, 49% also had lung hyperinflation. Twenty-three children had normal forced expiratory ratios but an increase of the ratio RV/TLC or of RV. When compared with children without lung hyperinflation, the age at diagnosis was significantly lower (3.9+/-1.9years vs 6.2+/-3.1years, p<0.01) and weight slightly lower (31+/-10kg vs 40+/-11kg, p=0.04). In conclusion, the use of plethysmography and thus the evaluation of pulmonary hyperinflation contributed to a better appreciation of the asthmatic phenotype in children.
Asunto(s)
Obstrucción de las Vías Aéreas/diagnóstico , Obstrucción de las Vías Aéreas/tratamiento farmacológico , Asma/diagnóstico , Asma/tratamiento farmacológico , Broncodilatadores/uso terapéutico , Mediciones del Volumen Pulmonar , Pletismografía/métodos , Administración por Inhalación , Adolescente , Corticoesteroides/efectos adversos , Corticoesteroides/uso terapéutico , Índice de Masa Corporal , Peso Corporal , Broncodilatadores/efectos adversos , Niño , Preescolar , Ritmo Circadiano , Progresión de la Enfermedad , Femenino , Volumen Espiratorio Forzado/efectos de los fármacos , Capacidad Residual Funcional , Humanos , Masculino , Estudios Retrospectivos , Espirometría , Capacidad Vital/efectos de los fármacosRESUMEN
Irrigation of povidone iodine considered as a safe and effective procedure, is frequently used for deep infections. We report a case of intoxication by iodine in a man of 68-year-old after subcutaneous irrigations of Betadine at a concentration of 20% for a subcutaneous infection of the thigh. Abnormalities of cardiac conduction, lactic acidosis, acute renal failure, hypocalcaemia and thyroid dysfunction were the manifestations of the intoxication confirmed by a very high level of total blood iodine and urine iodine.
Asunto(s)
Antiinfecciosos Locales/efectos adversos , Yodo/envenenamiento , Povidona Yodada/efectos adversos , Anciano , Antiinfecciosos Locales/uso terapéutico , Calcio/sangre , Creatinina/sangre , Humanos , Yodo/sangre , Yodo/orina , Lactatos/sangre , Masculino , Povidona Yodada/uso terapéutico , Enfermedades Cutáneas Infecciosas/complicaciones , Enfermedades Cutáneas Infecciosas/tratamiento farmacológico , Tejido Subcutáneo/patología , Irrigación Terapéutica/efectos adversosRESUMEN
2-Hydroxy-6-oxo-6-phenylhexa-2,4-dienoate (HOPDA) hydrolase (BphD) is a key determinant in the aerobic transformation of polychlorinated biphenyls (PCBs) by Burkholderia sp. strain LB400 (S. Y. K. Seah, G. Labbé, S. Nerdinger, M. Johnson, V. Snieckus, and L. D. Eltis, J. Biol. Chem. 275:15701-15708, 2000). To determine whether this is also true in divergent biphenyl degraders, the homologous hydrolase of Rhodococcus globerulus P6, BphD(P6), was hyperexpressed, purified to apparent homogeneity, and studied by steady-state kinetics. BphD(P6) hydrolyzed HOPDA with a k(cat)/K(m) of 1.62 (+/- 0.03) x 10(7) M(-1) s(-1) (100 mM phosphate [pH 7.5], 25 degrees C), which is within 70% of that of BphD(LB400). BphD(P6) was also similar to BphD(LB400) in that it catalyzed the hydrolysis of HOPDAs bearing chloro substituents on the phenyl moiety at least 25 times more specifically than those bearing chloro substituents on the dienoate moiety. However, the rhodococcal enzyme was significantly more specific for 9-Cl and 10-Cl HOPDAs, catalyzing the hydrolysis of 9-Cl, 10-Cl, and 9,10-diCl HOPDAs two- to threefold respectively, more specifically than HOPDA. Moreover, 4-Cl HOPDA competitively inhibited BphD(P6) more effectively than 3-Cl HOPDA, which is the inverse of what was observed in BphD(LB400). These results demonstrate that BphD is a key determinant in the aerobic transformation of PCBs by divergent biphenyl degraders, but that there exists significant diversity in the specificity of these biphenyl hydrolases.
Asunto(s)
Hidrolasas/metabolismo , Bifenilos Policlorados/metabolismo , Rhodococcus/enzimología , Biodegradación Ambiental , Evolución Molecular , Ácidos Grasos Insaturados/metabolismo , Hidrolasas/genética , Hidrolasas/aislamiento & purificación , Cinética , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Rhodococcus/genética , Especificidad por SustratoRESUMEN
The ability of 2-hydroxy-6-oxo-6-phenylhexa-2,4-dienoate (HOPDA) hydrolase (BphD) of Burkholderia cepacia LB400 to hydrolyze polychlorinated biphenyl (PCB) metabolites was assessed by determining its specificity for monochlorinated HOPDAs. The relative specificities of BphD for HOPDAs bearing chlorine substituents on the phenyl moiety were 0.28, 0.38, and 1.1 for 8-Cl, 9-Cl, and 10-Cl HOPDA, respectively, versus HOPDA (100 mm phosphate, pH 7.5, 25 degrees C). In contrast, HOPDAs bearing chlorine substituents on the dienoate moiety were poor substrates for BphD, which hydrolyzed 3-Cl, 4-Cl, and 5-Cl HOPDA at relative maximal rates of 2.1 x 10(-3), 1.4 x 10(-4), and 0.36, respectively, versus HOPDA. The enzymatic transformation of 3-, 5-, 8-, 9-, and 10-Cl HOPDAs yielded stoichiometric quantities of the corresponding benzoate, indicating that BphD catalyzes the hydrolysis of these HOPDAs in the same manner as unchlorinated HOPDA. HOPDAs also underwent a nonenzymatic transformation to products that included acetophenone. In the case of 4-Cl HOPDA, this transformation proceeded via the formation of 4-OH HOPDA (t(12) = 2.8 h; 100 mm phosphate, pH 7.5, 25 degrees C). 3-Cl HOPDA (t(12) = 504 h) was almost 3 times more stable than 4-OH HOPDA. Finally, 3-Cl, 4-Cl and 4-OH HOPDAs competitively inhibited the BphD-catalyzed hydrolysis of HOPDA (K(ic) values of 0.57 +/- 0. 04, 3.6 +/- 0.2, and 0.95 +/- 0.04 microm, respectively). These results explain the accumulation of HOPDAs and chloroacetophenones in the microbial degradation of certain PCB congeners. More significantly, they indicate that in the degradation of PCB mixtures, BphD would be inhibited, thereby slowing the mineralization of all congeners. BphD is thus a key determinant in the aerobic microbial degradation of PCBs.
Asunto(s)
Proteínas Bacterianas/metabolismo , Burkholderia cepacia/enzimología , Hidrolasas/metabolismo , Bifenilos Policlorados/metabolismo , Biodegradación Ambiental , Compuestos de Cloro/metabolismo , Ácidos Grasos Insaturados/metabolismo , Cinética , Espectroscopía de Resonancia Magnética , Estructura Molecular , Espectrofotometría , Especificidad por SustratoRESUMEN
Interleukin-2 (IL-2) has been shown to decrease cytochrome P450 (CYP) mRNAs and proteins in cultured rat hepatocytes, and IL-2 administration decreases CYPs in rats. Although high doses of IL-2 are administered to cancer patients, the effect on human CYPs has not yet been determined. Patients with hepatic metastases from colon or rectum carcinomas were randomly allocated to various daily doses of human recombinant IL-2 (from 0 to 12.10(6) units/m(2)). IL-2 was infused from day 7 to day 3 before hepatectomy and the conservation of a non-tumorous liver fragment in liquid nitrogen. Hepatic CYPs and monooxygenase activities were not significantly decreased in 5 patients receiving daily doses of 3 or 6 10(6) IL-2 units/m2, compared to 7 patients who did not receive IL-2. In contrast, in 6 patients receiving daily doses of 9 or 12 x 10(6) IL-2 units/m2, the mean values for immunoreactive CYP1A2, CYP2C, CYP2E1, and CYP3A4 were 37, 45, 60 and 39%, respectively, of those in controls; total CYP was significantly decreased by 34%, methoxyresorufin O-demethylation by 62%, and erythromycin N-demethylation by 50%. These observations suggest that high doses of IL-2 may decrease total CYP and monooxygenase activities in man.
Asunto(s)
Adenocarcinoma/enzimología , Antineoplásicos/farmacología , Neoplasias del Colon/enzimología , Sistema Enzimático del Citocromo P-450/metabolismo , Interleucina-2/farmacología , Neoplasias Hepáticas/enzimología , Neoplasias del Recto/enzimología , Adenocarcinoma/secundario , Adenocarcinoma/terapia , Antineoplásicos/uso terapéutico , Neoplasias del Colon/terapia , Citocromo P-450 CYP1A2/metabolismo , Citocromo P-450 CYP2E1/metabolismo , Citocromo P-450 CYP3A , Represión Enzimática , Humanos , Inmunoterapia , Interleucina-2/uso terapéutico , Neoplasias Hepáticas/inmunología , Neoplasias Hepáticas/secundario , Neoplasias Hepáticas/terapia , Oxigenasas de Función Mixta/metabolismo , Neoplasias del Recto/terapiaRESUMEN
BACKGROUND & AIMS: Interleukin (IL) 2 is used in advanced cancers, but its effects on cytochrome P450 remain unknown. Other cytokines down-regulate hepatic cytochrome P450, but it is not known whether this involves cytokine receptors. The aim of this study was to determine whether the IL-2 receptor is expressed on hepatocytes and whether its activation by IL-2 depresses cytochrome P450 in cultured rat hepatocytes. METHODS: A monoclonal antibody specific for the rat IL-2 receptor alpha chain was used to label the receptor, whereas effects on cytochrome P450 were determined after 24 hours of culture with human recombinant IL-2 (5000 U/mL). RESULTS: The presence of the IL-2 receptor in hepatocytes was shown by immunoblots, flow cytometry, and scanning confocal microscopy. IL-2 caused a 46% decrease in total cytochrome P450; a 35%, 35%, 36%, 26%, and 56% decrease in immunoreactive cytochrome P4501A1, 2B, 2C11, 2D1, and 3A, respectively; and a marked decrease in cytochrome P4503A2 and 2C11 messenger RNAs. Addition to the culture medium of the anti-receptor antibody or the tyrosine kinase inhibitor genistein prevented the IL-2-mediated decrease in cytochrome P450. CONCLUSIONS: IL-2 down-regulates the expression of cytochrome P450 genes in cultured rat hepatocytes by interacting with its receptor expressed on hepatocytes.
Asunto(s)
Sistema Enzimático del Citocromo P-450/metabolismo , Hígado/metabolismo , Receptores de Interleucina-2/fisiología , Animales , Anticuerpos Monoclonales , Secuencia de Bases , Células Cultivadas , Regulación hacia Abajo , Citometría de Flujo , Genisteína , Humanos , Immunoblotting , Interleucina-2/genética , Interleucina-2/fisiología , Isoflavonas/farmacología , Hígado/citología , Masculino , Microscopía Confocal , Datos de Secuencia Molecular , Proteínas Tirosina Quinasas/antagonistas & inhibidores , ARN Mensajero/análisis , Ratas , Ratas Sprague-DawleyRESUMEN
The article, part one of two in this issue, enables the nurse to follow a patient who receives an implantable defibrillator after surviving sudden cardiac death. Sudden cardiac death, which claims approximately 400,000 lives annually in the United States, is defined as natural, unexpected death due to cardiac causes, preceded by abrupt loss of consciousness within one hour of the onset of acute symptoms. It is generally caused by a complex interaction between a functional heart abnormality (such as ischemia) and an anatomic substrate (such as the myocardial scar tissue). Ventricular dysrrhythmias account for the majority of sudden cardiac deaths. This condition is treated with pharmaceutical antiarrhythmic agents or by implanting an internal cardioverter defibrillator. The equipment and surgery using the transvenous approach are described here. Specific nursing care during the postoperative period is also explained. Finally, the authors present several recommendations related to the convalescent period at home.
Asunto(s)
Desfibriladores Implantables , Isquemia Miocárdica/terapia , HumanosRESUMEN
Implantable defibrillators have created a new cardiac population. But with that population come particular needs. Eighty-five per cent of patients with implantable defibrillators experience significant fears and worries. Many of them fear the first shock or worry about the device's reliability. Others wonder if they will be able to remain in their current occupation. Despite these worries and others, 60 per cent of patients state being satisfied with the device. On the other hand, 53 per cent of these patients' spouses still fear the defibrillators. The authors of this article underline that nurses must learn to intervene appropriately to meet their patients' physical, learning and psychosocial needs. The nurse's responsibilities are to help patients identify their social support system and mobilize their resources, and to help family members in meeting patients' needs.
Asunto(s)
Desfibriladores Implantables , Depresión/enfermería , Humanos , Apoyo SocialRESUMEN
Human recombinant interleukin-2 (IL-2) administration is being tested in patients with advanced cancer. Its effects on the expression of cytochromes P-450 were determined in rats. IL-2 administration (1-25 x 10(6) U/kg i.v. twice daily for 1 to 4 days) resulted in a time- and dose-dependent decrease in cytochrome P-450 measured by the absorbance of its Fe(++)-CO complex. After 25 x 10(6) U/kg twice daily for 4 days, cytochrome P-450 decreased 44%; immunoreactive cytochrome P-450 1A1 decreased nonsignificantly (22%); but cytochrome P-450 1A2 decreased 68%; 2B1/2, 50%; 2C11, 75%; 2D1, 36%; and 3A, 70%. Aminopyrine N-demethylase activity decreased 53%, ethoxycoumarin O-deethylase 64%, benzo(a)pyrene hydroxylase 71%, ethoxyresorufin O-deethylase 42%, pentoxyresorufin O-dealkylase 81% and erythromycin N-demethylase 56%. In rats treated with 3-methylcholanthrene for 4 days, IL-2 coadministration (25 x 10(6) U/kg i.v. twice daily for 4 days) did not decrease significantly immunoreactive cytochrome P-450 1A1 and 1A2, whereas cytochromes P-450 2B1/2, 2C11 and 3A decreased 39, 54 and 67%, respectively. In rats treated with phenobarbital for 4 days, IL-2 coadministration decreased immunoreactive cytochromes P-450 2B1/2 29%, whereas cytochromes P-450 1A2, 2C11 and 3A decreased 38, 63 and 67%, respectively. We conclude that administration of high doses of IL-2 decreases the expression of several cytochromes P-450 in rats. Microsomal enzyme inducers appear to limit the effects of IL-2 on the induced forms of cytochromes P-450. Because much lower doses are used in humans, their potential effects on drug metabolism cannot be assessed from present results.
Asunto(s)
Sistema Enzimático del Citocromo P-450/biosíntesis , Interleucina-2/farmacología , Isoenzimas/metabolismo , Animales , Monóxido de Carbono/metabolismo , Citocromos b5/metabolismo , Interacciones Farmacológicas , Humanos , Hígado/anatomía & histología , Masculino , Metilcolantreno/farmacología , Microsomas Hepáticos/enzimología , NADPH-Ferrihemoproteína Reductasa/metabolismo , Tamaño de los Órganos , Fenobarbital/farmacología , Ratas , Ratas Sprague-Dawley , Proteínas Recombinantes/farmacologíaRESUMEN
Amiodarone has been shown to produce microvesicular steatosis of the liver in some recipients. We have determined the effects of amiodarone on the mitochondrial oxidation of fatty acids in mice. In vitro, the formation of 14C-acid-soluble beta-oxidation products from [U-14C]palmitic acid by mouse liver mitochondria was decreased by 92% in the presence of 125 microM amiodarone and by 94% in the presence of 125 microM N-desethylamiodarone. Inhibition due to 100 or 150 microM amiodarone persisted in the presence of 5 mM acetoacetate, whereas acetoacetate totally relieved inhibition due to 15 microM rotenone. In vivo, exhalation of [14C]CO2 from [U-14C]palmitic acid was decreased by 31, 40, 58 and 78%, respectively, in mice receiving 19, 25, 50 and 100 mg.kg-1 of amiodarone hydrochloride 1 hr before the administration of [U-14C]palmitic acid. One hour after 100 mg.kg-1, the exhalation of [14C]CO2 from [1-14C]palmitic acid, [1-14C]octanoic acid or [1-14C]butyric acid was decreased by 78, 72 and 53%, respectively. Exhalation of [14C]CO2 from [1-14C]palmitic acid was normal between 6 and 9 hr after administration of 100 mg.kg-1 of amiodarone hydrochloride, but was still inhibited by 71 and 37%, 24 and 48 hr after 600 mg.kg-1. Twenty four hours after the latter dose of amiodarone, hepatic triglycerides were increased by 150%, and there was microvesicular steatosis of the liver. We conclude that amiodarone inhibits the mitochondrial beta-oxidation of fatty acids and produces microvesicular steatosis of the liver in mice.
Asunto(s)
Amiodarona/farmacología , Necrosis Grasa/inducido químicamente , Ácidos Grasos/metabolismo , Hígado/metabolismo , Mitocondrias Hepáticas/metabolismo , Animales , Dióxido de Carbono/metabolismo , Radioisótopos de Carbono , Relación Dosis-Respuesta a Droga , Cuerpos Cetónicos/sangre , Metabolismo de los Lípidos , Hígado/citología , Hígado/efectos de los fármacos , Hígado/ultraestructura , Masculino , Ratones , Mitocondrias Hepáticas/efectos de los fármacos , Oxidación-Reducción/efectos de los fármacosRESUMEN
The effects of the R-(-) and S-(+)ibuprofen enantiomers were first studied in vitro with mouse liver mitochondria incubated in the presence of various concentrations of exogenous coenzyme A. In the presence of a low concentration of coenzyme A (2.5 microM), the R-(-)enantiomer (which forms an acylcoenzyme A) inhibited stereoselectively the beta oxidation of [1-14C]palmitic acid but not that of [1-14C]palmitoyl-L-carnitine (which can directly enter the mitochondria). In the presence, however, of a concentration of coenzyme A (50 microM) reproducing that present in liver cell cytosol, both enantiomers (2 mM) slightly inhibited the beta oxidation of [1-14C]palmitic acid and markedly inhibited the beta oxidation of [1-14C]octanoic acid and [1-14C]butyric acid. In vivo, both enantiomers (1 mmol.kg-1) similarly inhibited the formation of [14C]CO2 from [1-14C]fatty acids. Both enantiomers similarly decreased plasma ketone bodies. Both similarly increased hepatic triglycerides, and both produced mild microvesicular steatosis of the liver. We conclude that both ibuprofen enantiomers inhibit beta oxidation of fatty acids in vitro and in vivo. In addition, the R-(-)enantiomer may stereoselectively sequester coenzyme A; at low concentrations of coenzyme A in vitro, this may stereoselectively inhibit the mitochondrial uptake and beta oxidation of long chain fatty acids.
Asunto(s)
Ácidos Grasos/metabolismo , Ibuprofeno/farmacología , Mitocondrias Hepáticas/efectos de los fármacos , Animales , Dióxido de Carbono/metabolismo , Radioisótopos de Carbono , Técnicas In Vitro , Cuerpos Cetónicos/sangre , Metabolismo de los Lípidos , Masculino , Ratones , Ratones Endogámicos ICR , Mitocondrias Hepáticas/metabolismo , Oxidación-Reducción , Ratas , Ratas Endogámicas , EstereoisomerismoRESUMEN
Administration of troleandomycin (0.5 mmol.kg-1 p.o. daily for 5 days) decreased by 61% and 36%, respectively, the estradiol and ethinylestradiol 2/4-hydroxylase activities of hepatic microsomes from male Sprague-Dawley rats killed 2 hr after the last dose. This decrease did not appear to be due to the in vivo formation of the inactive cytochrome P-450 p Fe(II)-metabolite complex, since disruption of this complex with potassium ferricyanide did not increase estrogen hydroxylase activities. Troleandomycin administration, however, essentially suppressed cytochrome P-450 UT-A (one of the P-450 forms involved in the hydroxylation of estrogens) and resulted in the appearance of cytochrome P-450 forms whose estradiol hydroxylase activity was inhibitable by troleandomycin in vitro. Similarly, troleandomycin (2 mM) inhibited by 60% estradiol and ethinylestradiol 2/4-hydroxylase activities in microsomes from dexamethasone-treated rats, although it had no inhibitory effect in microsomes from control rats. In contrast, erythromycin and roxithromycin (2 mM) exerted no inhibitory effect, even in microsomes from dexamethasone-treated rats. In vivo, these macrolides (0.5 mmol.kg-1 p.o. daily for 5 days) decreased moderately cytochrome P-450 UT-A levels and estradiol 2/4-hydroxylase activity, and did not modify ethinylestradiol 2/4-hydroxylase activity. We conclude that the administration of troleandomycin, but not that of erythromycin or roxithromycin, decreases ethinylestradiol 2/4-hydroxylase activity in male rat liver microsomes, as a possible consequence of decreased cytochrome P-450 UT-A levels and of the induction of glucocorticoid-responsive P-450 forms whose ethinylestradiol hydroxylase activity is inhibitable by troleandomycin.
Asunto(s)
Citocromo P-450 CYP1A1 , Inhibidores Enzimáticos del Citocromo P-450 , Eritromicina/farmacología , Microsomas Hepáticos/efectos de los fármacos , Roxitromicina/farmacología , Esteroide Hidroxilasas/antagonistas & inhibidores , Troleandomicina/farmacología , Animales , Sistema Enzimático del Citocromo P-450/metabolismo , Dexametasona/farmacología , Ferricianuros/farmacología , Masculino , Microsomas Hepáticos/enzimología , Ratas , Ratas Endogámicas , Esteroide Hidroxilasas/metabolismoRESUMEN
Administration of silymarin (800 mg/kg i.p.) 30 min before carbon tetrachloride (18 microL/kg i.p.) did not modify total hepatic levels of CCl4 and metabolites in mice, but decreased by 40% the in vivo covalent binding of CCl4 metabolites to hepatic lipids at 2 hr. This pretreatment decreased by 60% the exhalation of ethane during the first hour after CCl4, and decreased by 50% the incidence of liver cell necrosis. In vitro, silymarin (800 micrograms/mL) decreased by 50 to 70% various monooxygenase activities, and decreased by 20% the covalent binding of CCl4 metabolites to microsomal proteins. Silymarin (800 micrograms/mL) decreased by 70% in vitro lipid peroxidation mediated by CCl4 metabolites, and decreased by 90% peroxidation mediated by NADPH alone. Silibinin, one of the three isomers composing silymarin, also decreased carbon tetrachloride-induced lipid peroxidation; this effect, however, was less than that of silymarin in vitro, and was more transient in vivo. Pretreatment with silibinin (800 mg/kg i.p.) 30 min before CCl4 (18 microL/kg i.p.) did not improve SGPT activity or liver histology at 24 hr. We conclude that silymarin prevents carbon tetrachloride-induced lipid peroxidation and hepatotoxicity in mice, firstly, by decreasing the metabolic activation of CCl4, and, secondly, by acting as a chain-breaking antioxidant.
Asunto(s)
Antioxidantes/farmacología , Tetracloruro de Carbono/antagonistas & inhibidores , Flavonoides/farmacología , Peroxidación de Lípido/efectos de los fármacos , Hígado/efectos de los fármacos , Silimarina/farmacología , 7-Alcoxicumarina O-Dealquilasa/metabolismo , Alanina Transaminasa/sangre , Animales , Unión Competitiva , Tetracloruro de Carbono/toxicidad , Inyecciones Intraperitoneales , Hígado/patología , Masculino , RatonesRESUMEN
Tianeptine is a new tricyclic antidepressant which is metabolized mainly by beta-oxidation of its heptanoic side chain. We determined the effects of tianeptine on the mitochondrial oxidation of natural fatty acids in mice. In vitro, tianeptine (0.5 mM) inhibited by only 32% the formation of beta-oxidation products from [1-14C]palmitic acid by hepatic mitochondria, but inhibited by 71% that from [1-14C]octanoic acid and by 51% that from [1-14C]butyric acid. The activity of the tricarboxylic acid cycle, assessed as the in vitro formation of [14C]CO2 from [1-14C]acetylcoenzyme A was decreased by 51% in the presence of tianeptine (0.5 mM). The inhibition of both beta-oxidation and the tricarboxylic acid cycle appeared reversible in mitochondria from mice exposed to tianeptine in vivo but incubated in vitro without tianeptine. In vivo, administration of tianeptine (0.0625 mmol/kg i.p.), decreased by 53 and 58%, respectively, the formation of [14C]CO2 from [1-14C]octanoic acid and [1-14C]butyric acid, but did not significantly decrease that from [1-14C]palmitic acid. After administration of high doses of tianeptine, however, formation of [14C]CO2 from [1-14C]palmitic acid became inhibited as well, transiently after 0.25 mmol/kg and durably (greater than 24 hr) after 0.75 mmol/kg i.p. Hepatic triglycerides were increased 24 hr after administration of 0.75 mmol/kg i.p. of tianeptine, but not after 0.25 mmol/kg i.p. Microvesicular steatosis of the liver was observed in some mice after 0.75 mmol/kg i.p., but not after 0.5 mmol/kg i.p. We conclude that tianeptine inhibits the oxidation of medium- and short-chain fatty acids in mice. Microvesicular steatosis, however, requires very large doses in mice (0.75 mmol/kg i.p., i.e. 600-times the oral dose in humans), and is therefore unlikely to occur in humans.
Asunto(s)
Antidepresivos Tricíclicos/metabolismo , Ácidos Grasos/metabolismo , Ácidos Heptanoicos/metabolismo , Mitocondrias Hepáticas/efectos de los fármacos , Tiazepinas/metabolismo , Animales , Antidepresivos Tricíclicos/farmacología , Glucemia/análisis , Ácidos Grasos/análisis , Hígado Graso/inducido químicamente , Hígado Graso/metabolismo , Cuerpos Cetónicos/sangre , Masculino , Ratones , Mitocondrias Hepáticas/análisis , Mitocondrias Hepáticas/metabolismo , Estructura Molecular , Oxidación-Reducción/efectos de los fármacos , Tiazepinas/farmacología , Factores de Tiempo , Triglicéridos/análisis , Triglicéridos/metabolismoRESUMEN
Incubation under air of [14C]tianeptine (0.5 mM) with a NADPH-generating system and hamster, mouse or rat liver microsomes resulted in the in vitro covalent binding of [14C]tianeptine metabolites to microsomal proteins. Covalent binding to hamster liver microsomes required NADPH and oxygen; it was decreased in the presence of the cytochrome P-450 inhibitors, carbon monoxide, piperonyl butoxide (4 mM), and SKF 525-A (4 mM) or in the presence of the nucleophile, glutathione (1 or 4 mM). In vitro covalent binding to hamster liver microsomes was not decreased in the presence of quinidine (1 microM), and was similar with microsomes from either female Dark Agouti, or female Sprague-Dawley rats. In contrast, in vitro covalent binding to hamster liver microsomes was decreased in the presence of troleandomycin (0.25 mM), while covalent binding was increased with microsomes from either hamsters, mice or rats pretreated with dexamethasone. Preincubation with IgG antibodies directed against rabbit liver glucocorticoid-inducible cytochrome P-450 3c(P-450 IIIA4) decreased in vitro covalent binding by 53 and 89%, respectively, with microsomes from control hamsters and dexamethasone-pretreated hamsters, and by 60 and 81%, respectively, with microsomes from control and dexamethasone-pretreated rats. We conclude that tianeptine is activated by hamster, mouse and rat liver cytochrome P-450 into a reactive metabolite. Metabolic activation is mediated in part by glucocorticoid-inducible isoenzymes but not by the isoenzyme metabolizing debrisoquine. In vivo studies are reported in the accompanying paper.
Asunto(s)
Antidepresivos Tricíclicos/metabolismo , Sistema Enzimático del Citocromo P-450/fisiología , Tiazepinas/metabolismo , Animales , Biotransformación , Cricetinae , Dexametasona/farmacología , Técnicas In Vitro , Masculino , Mesocricetus , Ratones , Microsomas Hepáticos/metabolismo , Ratas , Ratas EndogámicasRESUMEN
Administration of [14C]tianeptine (0.5 mmol/kg i.p.) to non-pretreated hamsters resulted in the in vivo covalent binding of [14C]tianeptine metabolites to liver, lung and kidney proteins; this very high dose (360-fold the human therapeutic dose) depleted hepatic glutathione by 60%, and increased SGPT activity 5-fold. Lower doses (0.25 and 0.125 mmol/kg) depleted hepatic glutathione to a lesser extent and did not increase SGPT activity. Pretreatment of hamsters with piperonyl butoxide decreased in vivo covalent binding to liver proteins, and prevented the increase in SGPT activity after administration of tianeptine (0.5 mmol/kg i.p.). In contrast, pretreatment of hamsters with dexamethasone increased in vivo covalent binding to liver proteins, and increased SGPT activity after administration of tianeptine (0.5 mmol/kg i.p.). Nevertheless, liver cell necrosis was histologically absent 24 hr after the administration of tianeptine (0.5 mmol/kg i.p.) to non-pretreated or dexamethasone-pretreated hamsters. In vivo covalent binding to liver proteins also occurred in mice and rats, being increased by 100% in dexamethasone-pretreated animals. In vivo covalent binding to liver proteins was similar in untreated female Dark Agouti rats and in female Sprague-Dawley rats. These results show that tianeptine is transformed in vivo by cytochrome P-450, including glucocorticoid-inducible isoenzymes, into chemically reactive metabolites that covalently bind to tissue proteins. The metabolites, however, exhibit no direct hepatotoxic potential in hamsters below the sublethal dose of 0.5 mmol/kg i.p. The predictive value of this study regarding possible idiosyncratic and immunoallergic reactions in humans remains unknown.
Asunto(s)
Antidepresivos Tricíclicos/metabolismo , Tiazepinas/metabolismo , Alanina Transaminasa/sangre , Animales , Biotransformación , Cricetinae , Femenino , Glutatión/análisis , Hígado/efectos de los fármacos , Hígado/patología , Masculino , Mesocricetus , Ratones , Ratones Endogámicos ICR , Unión Proteica , Ratas , Ratas Endogámicas , Tiazepinas/toxicidadRESUMEN
Incubation of rat liver microsomes with [3H]methoxsalen and NADPH resulted in the covalent binding of a methoxsalen intermediate to proteins comigrating with cytochromes P-450 UT-A, PB-B/D, ISF-G and PCN-E. Binding was increased by pretreatments with phenobarbital, beta-naphthoflavone (beta NF) and dexamethasone. Such pretreatments also increased the loss of CO-binding capacity either after administration of methoxsalen, or after incubation of hepatic microsomes with methoxsalen and NADPH. Immunoprecipitation of the methoxsalen metabolite-protein adducts in phenobarbital-induced microsomes was moderate with anti-UT-A antibodies, but marked with anti-PB-B/D and anti-PCN-E antibodies. Immunoprecipitation was observed also with anti-ISF-G (anti-beta NF-B) antibodies in beta NF-induced microsomes. Methoxsalen (0.25 mM) inhibited markedly the benzphetamine demethylase activity of phenobarbital-induced microsomes and the erythromycin demethylase activity of dexamethasone-induced microsomes. Whereas methoxsalen itself did not produce any binding spectrum, in contrast either in vivo administration of methoxsalen or incubation in vitro with methoxsalen and NADPH resulted in a low-to-high spin conversion of cytochrome P-450 as suggested by the appearance of a spectrum analogous to a type I binding spectrum. This low-to-high spin conversion was apparently due to a methoxsalen intermediate (probably, covalently bound to the protein and preventing partial sixth ligation of the iron). We conclude that suicide inactivation of cytochrome P-450 by methoxsalen is related to the covalent binding of a methoxsalen intermediate to the protein moiety of several cytochrome P-450 isoenzymes (including UT-A, PB-B/D, PCN-E as well as ISF-G and/or beta NF-B).