RESUMEN
BACKGROUND: Vascular complications are still common in the catheterization laboratory setting. However, no risk scores for their prediction have been described. With a view to bridging this gap, the present study sought to develop and validate a score for prediction of vascular complications associated with arterial access in patients undergoing interventional cardiology procedures. METHODS: This prospective multicenter cohort study included adult patients who underwent cardiac catheterization via the femoral or radial route. The outcomes of interest were: access site hematoma; major and minor bleeding; and retroperitoneal hemorrhage, pseudoaneurysm, or arteriovenous fistula requiring surgical repair. Past medical history as well as pre-procedural, intra-procedural, and post-procedural variables were collected. Patients were randomly allocated to the derivation or validation cohorts at a 2:1 ratio. The following equation constituted the score: (>6F introducer sheath×4.0)+(percutaneous coronary intervention×2.5)+(history of vascular complication after prior interventional cardiology procedure×2.0)+(prior use of warfarin or phenprocoumon×2.0)+(female sex×1.5)+(age⩾60 years×1.5). The maximum score is 13.5 points. RESULTS: A score dichotomized at ⩾3 (best cutoff for balancing sensitivity and specificity) was moderately accurate (sensitivity=0.66 (95% confidence interval: 0.59-0.73); specificity=0.59 (95% confidence interval: 0.56-0.61)). Patients with a score ⩾3 were at increased risk of complications (odds ratio: 2.95; 95% confidence interval: 2.22-3.91). CONCLUSIONS: This study yielded a score that is capable of predicting vascular complications and easily applied in daily practice by providers working in the catheterization laboratory setting.
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Cateterismo Cardíaco/efectos adversos , Cateterismo Cardíaco/normas , Procedimientos Quirúrgicos Cardíacos/efectos adversos , Procedimientos Quirúrgicos Cardíacos/normas , Complicaciones Posoperatorias/etiología , Medición de Riesgo/normas , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Cohortes , Femenino , Humanos , Masculino , Persona de Mediana Edad , Oportunidad Relativa , Valor Predictivo de las Pruebas , Estudios ProspectivosRESUMEN
Atomoxetine is a cytochrome P4502D6 (CYP2D6) substrate. The reduced-activity CYP2D6*10 allele is particularly prevalent in the Japanese population and may contribute to known ethnic differences in CYP2D6 metabolic capacity. The purpose of this study was to examine atomoxetine pharmacokinetics, safety, tolerability, and the effect of the CYP2D6*10/*10 genotype after single-stepped dosing (10, 40, 90, or 120 mg) and at steady state (40 or 60 mg twice a day for 7 days) in 49 healthy Japanese adult men. Dose proportionality was shown and tolerability confirmed at all doses studied. Comparison of pharmacokinetics, safety, and tolerability between Japanese and US subjects showed no clinically meaningful ethnic differences. The CYP2D6*10/*10 subjects had 2.1- to 2.2-fold and 1.8-fold higher area under the plasma concentration-time curve values relative to the CYP2D6*1/*1 and *1/*2 subjects and the CYP2D6*1/*10 and *2/*10 subjects, respectively. The adverse events reported by CYP2D6*10/*10 subjects were indistinguishable from those of other Japanese participants. The higher mean exposure in CYP2D6*10/*10 subjects is not expected to be clinically significant.
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Pueblo Asiatico/genética , Citocromo P-450 CYP2D6/genética , Citocromo P-450 CYP2D6/metabolismo , Propilaminas/efectos adversos , Propilaminas/farmacocinética , Inhibidores de Captación Adrenérgica/efectos adversos , Inhibidores de Captación Adrenérgica/farmacocinética , Adulto , Área Bajo la Curva , Clorhidrato de Atomoxetina , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Regulación Enzimológica de la Expresión Génica , Genotipo , Semivida , Humanos , Masculino , Adulto JovenRESUMEN
Methyleugenol is a substituted alkenylbenzene found in a variety of foods, products, and essential oils. In a 2-year bioassay conducted by the National Toxicology Program, methyleugenol caused neoplastic lesions in the livers of Fischer 344 rats and B6C3F(1) mice. We were interested in the cytotoxicity and genotoxicity caused by methyleugenol and other alkenylbenzene compounds: safrole (a known hepatocarcinogen), eugenol, and isoeugenol. The endpoints were evaluated in cultured primary hepatocytes isolated from male Fischer 344 rats and female B6C3F(1) mice. Cytotoxicity was determined by measuring lactate dehydrogenase (LDH) release, while genotoxicity was determined by using the unscheduled DNA synthesis (UDS) assay. Rat and mouse hepatocytes showed similar patterns of toxicity for each chemical tested. Methyleugenol and safrole were relatively non-cytotoxic, but caused UDS at concentrations between 10 and 500 microM. In contrast, isoeugenol and eugenol produced cytotoxicity in hepatocytes with LC50s of approximately 200-300 microM, but did not cause UDS. Concurrent incubation of 2000 microM cyclohexane oxide (CHO), an epoxide hydrolase competitor, with a non-cytotoxic concentration of methyleugenol (10 microM) resulted in increased cytotoxicity but had no effect on genotoxicity. However, incubation of 15 microM pentacholorophenol, a sulfotransferase inhibitor, with 10 uM methyleugenol resulted in increased cytotoxicity but had a significant reduction of genotoxicity. These results suggest that methyleugenol is similar to safrole in its ability to cause cytotoxicity and genotoxicity in rodents. It appears that the bioactivation of methyleugenol to a DNA reactive electrophile is mediated by a sulfotransferase in rodents, but epoxide formation is not responsible for the observed genotoxicity.
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Eugenol/análogos & derivados , Eugenol/toxicidad , Mutágenos/toxicidad , Animales , Reparación del ADN , Femenino , L-Lactato Deshidrogenasa/metabolismo , Hígado/citología , Hígado/efectos de los fármacos , Hígado/enzimología , Masculino , Ratones , Ratas , Ratas Endogámicas F344RESUMEN
In rats and mice, 1-nitronaphthalene (1-NN) produces both lung and liver toxicity. Even though these toxicities have been reported, the metabolism and disposition of 1-NN have not been elucidated. Therefore, studies were performed to characterize its fate after i.p. and i.v. administration to male Sprague-Dawley rats. After i.p. administration of [(14)C]1-NN (100 mg/kg; 60 microCi/kg), 84% of the dose was eliminated in the urine and feces by 48 h. At 96 h, 60% of the dose was recovered in the urine, 32% in the feces, and 1% collectively in the tissues, blood, and gastrointestinal contents. The terminal phase rate constant (k(term)) of 1-NN was 0.21 h(-1), the terminal phase half-life (T(1/2,term)) was 3.40 h, and the systemic bioavailability was 0.67. When administered i.v. (10 mg/kg; 120 microCi/kg), 85% of the dose was eliminated in the urine and feces by 24 h. At the end of the study (96 h), 56% of the dose was recovered in the urine, 36% in the feces, and 1% collectively in the tissues, blood, and gastrointestinal contents. Interestingly, 88% of the dose was secreted into bile by 8 h. The k(term) was 0.94 h(-1) and the T(1/2,term) was 0.77 h. The major urinary metabolite after both routes of administration was N-acetyl-S-(hydroxy-1-nitro-dihydronaphthalene)-L-cysteine. Other urinary metabolites identified include hydroxylated, dihydroxylated, glucuronidated, sulfated, and reduced metabolites, as well as dihydrodiol. The major biliary metabolite was hydroxy-glutathionyl-1-nitro-dihydronaphthalene. These data show that 1-NN undergoes extensive metabolism and enterohepatic recirculation, and the majority of the dose is eliminated in the urine.
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Carcinógenos/metabolismo , Naftalenos/metabolismo , Animales , Bilis/metabolismo , Sistema Biliar/metabolismo , Radioisótopos de Carbono , Carcinógenos/farmacocinética , Inyecciones Intraperitoneales , Inyecciones Intravenosas , Hígado/efectos de los fármacos , Pulmón/efectos de los fármacos , Masculino , Tasa de Depuración Metabólica , Naftalenos/farmacocinética , Naftalenos/orina , Ratas , Ratas Sprague-DawleyRESUMEN
1,2-Dibromo-2,4-dicyanobutane (BCB) is a broad-spectrum microbicide used commercially in consumer products. The objectives of this study were to elucidate the biotransformation of BCB, characterize its ability to covalently bind macromolecules, and predict the possible toxicological ramifications of such events. After iv administration of [14C]BCB to male Fischer 344 rats, 14C-equivalents were observed to bind gradually to blood constituents. By 48 hr, approximately 12% of the total dose was covalently bound. At no time was parent compound detected in the blood. However, the debrominated BCB metabolite 2-methyleneglutaronitrile (MGN) was observed. In vitro experiments revealed that BCB was extremely labile and was readily debrominated in fresh whole blood, erythrocyte preparations, and buffered glutathione (GSH) solutions. In each case, the formation of MGN was inhibited by the alkylation of free sulfhydryls with N-ethylmaleimide (NEM). For every 1 mol of BCB converted to MGN, 2 mol of GSH were oxidized to glutathione disulfide (GSSG) (BCB + 2 GSH --> MGN + GSSG + 2 HBr). The oxidation of free sulfhydryls during the conversion of BCB to MGN caused erythrocyte hemolysis (EC50 approximately 1 mM) in isolated preparations. Hemolysis was increased by coincubation of BCB with NEM (EC50 approximately 0.3 mM) and was decreased by coincubation with GSH (EC50 > 3 mM). However, MGN did not cause hemolysis of erythrocytes, even at concentrations 10-fold higher than the EC50 of BCB. In vitro experiments also demonstrated that incubation with either BCB or MGN resulted in significant macromolecular binding to the erythrocyte fraction of the blood (approximately 80%). Incubation with NEM resulted in a significant decrease in binding for both BCB (11.3% bound) and MGN (29.5% bound). Because BCB is rapidly debrominated in whole blood, it appears that MGN is the reactive species responsible for macromolecular binding. From these studies, we conclude that the conversion of BCB to MGN is mediated by a free sulfhydryl-dependent biotransformation pathway. Furthermore, BCB biotransformation is required for erythrocyte binding, and the consumption of free sulfhydryls associated with the biotransformation of BCB is responsible for hemolysis.
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Antiinfecciosos/farmacocinética , Nitrilos/farmacocinética , Animales , Antiinfecciosos/sangre , Biotransformación , Supervivencia Celular , Eritrocitos/citología , Eritrocitos/metabolismo , Glutatión , Masculino , Espectrometría de Masas , Nitrilos/sangre , Ratas , Ratas Endogámicas F344RESUMEN
Studies were conducted to characterize the absorption, disposition, metabolism, and excretion of 1,2-dibromo-2,4-dicyanobutane (BCB; methyldibromoglutaronitrile) following iv, oral, and topical administration to male Fischer 344 rats. Following iv administration of [14C]BCB (8 mg/kg, 120 microCi/kg), no parent compound was detected in the blood; however, its debrominated metabolite, 2-methyleneglutaronitrile (2-MGN; Cmax 7.3 micrograms/ml), was observed up to 1 hr. Within 72 hr, greater than 60% of the dose was excreted in the urine and 4.1% in the feces, and 6.6% was exhaled as 14CO2. Although less than 5% of the dose was retained in tissues, approximately 12% was bound to the erythrocyte fraction of the blood. Following oral administration of [14C]BCB (80 mg/kg, 100 microgramsCi/kg), approximately 85% of the dose was absorbed, whereas 72% of the dosed radioactivity was recovered in the urine and 9.7% in the feces, 7.5% was exhaled as 14CO2, 3.5% bound to tissues, and 2. 6% bound to blood. Although parent compound could not be detected in the blood following oral administration, 2-MGN was detected (Cmax 0. 32 micrograms/ml). Following topical application of [14C]BCB (25 mg/kg, 50 microgramsCi/kg), less than 12% of the dose was absorbed, with the major route of excretion being the urine (6.6% of dose). Urinary metabolite profiles were nearly identical for each route of administration, and the primary urinary metabolite was a mercapturate conjugate of 2-MGN that was identified as N-acetyl-S-(2, 4-dicyanobutane)-L-cysteine. BCB was found to be extremely labile in whole blood, plasma, and glutathione containing solutions, and in each case the formation of 2-MGN could be reduced by the alkylation of free-sulfhydryls with N-ethylmaleimide. These results suggest that BCB is totally debrominated prior to systemic distribution, and tissue exposure to intact BCB seems to be exceedingly low regardless of route of administration.
Asunto(s)
Nitrilos/farmacocinética , Conservadores Farmacéuticos/farmacocinética , Animales , Cromatografía Líquida de Alta Presión , Relación Dosis-Respuesta a Droga , Masculino , Espectrometría de Masas , Nitrilos/administración & dosificación , Conservadores Farmacéuticos/administración & dosificación , Ratas , Ratas Endogámicas F344RESUMEN
This study was conducted to compare the effects of 60-day dietary exposure (2%) to low melt point paraffin wax (LMPW) on both general liver morphology and Kupffer cell (KC) function and morphology in female F-344 and Sprague-Dawley (SD) rats. Livers from only F-344 rats fed LMPW had granuloma formation/lymphoid cell aggregates with small areas of necrosis. Significant increases in serum alanine and aspartate aminotransferase as well as gamma-glutamyltransferase activities were detected only in treated F-344 rats. Additionally, detectable amounts of LMPW were present only in livers of treated F-344 rats. Because KC can be involved in granuloma formation, their morphology and function were examined. Electron microscopy revealed the presence of large, irregularly shaped, membrane-associated vacuoles in cells isolated from F-344 rats exposed to LMPW. These vacuoles were not seen in KC from control rats and rarely detected in KC isolated from LMPW-exposed SD rats. Moreover, indices of KC function including phagocytic activity and nitric oxide and superoxide anion production were significantly increased by KC isolated from F-344 rats exposed to LMPW (1.6-, 36-, and 2.2-fold increases, respectively) over untreated controls. In contrast, LPS-stimulated production of TNF and LTB4 was significantly decreased only in KC of LMPW-fed F-344 rats. No significant changes in these functions were observed in KC isolated from SD rats exposed to LMPW or from KC isolated from control F-344 or SD rats. These data provide evidence that dietary LMPW alters the morphology and functional capacity of KC of F-344 but not SD rats and these changes may ultimately lead to granuloma formation.
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Macrófagos del Hígado/efectos de los fármacos , Parafina/toxicidad , Animales , Peso Corporal/efectos de los fármacos , Enzimas/sangre , Femenino , Macrófagos del Hígado/ultraestructura , Recuento de Leucocitos , Leucotrieno B4/biosíntesis , Hígado/metabolismo , Nitritos/metabolismo , Fagocitosis/efectos de los fármacos , Ratas , Ratas Endogámicas F344 , Ratas Sprague-Dawley , Especificidad de la Especie , Superóxidos/metabolismo , Factor de Necrosis Tumoral alfa/biosíntesisRESUMEN
trans-Methyl styryl ketone (MSK; trans-4-phenyl-3-buten-2-one) is a beta-unsaturated ketone that has a wide range of uses in industry, as well as consumer products. MSK does not appear to be overtly toxic in animal models, however, it has been shown to be mutagenic in several in vitro assays after S-9 activation. In this study experiments were conducted to characterize MSK absorption, distribution, metabolism, and elimination after iv, oral, and topical administration to female B6C3F1 mice. After iv administration, [14C]MSK (20 mg/kg; 120 microCi/kg) was rapidly cleared from the blood as evidenced by the following pharmacokinetic values (mean +/- SD): terminal disposition half-life (t1/2), 7.98 +/- 1.72 min; mean residence time, 5.6 +/- 1.7 min; steady-state apparent volume of distribution (Vss), 3.33 +/- 0.75 liters/kg; and systemic body clearance (CLs), 0.53 +/- 0.05 liters/min/kg. Within 48 hr, 92.4% of the dose was excreted in the urine and 3.5% in the feces. The major blood metabolites after iv administration were identified by GC-MS as the 4-phenyl-3-buten-2-ol (methyl styryl carbinol), 4-hydroxy-4-phenyl-2-butanone, and benzyl alcohol. After oral administration of [14C]MSK (200 mg/kg; 100 microCi/kg), 95% of the dosed radioactivity was recovered in the urine and 1.2% in the feces within 48 hr. Major urinary metabolites were identified by LC-MS/MS as N-phenylacetyl-l-glycine (35.1% of dose) and N-benzyl-L-glycine (19.1% of dose). Only a small amount of MSK was detected in the blood after oral administration ( approximately 0.73 microg/ml at 10 min), and [14C]-equivalents in the blood never exceeded 2.8% of the dose. Ater topical application of [14C]MSK (250 mg/kg; 50 microCi/kg), approximately 40% of the dose was absorbed and 84.5% of the absorbed dose was excreted into the urine (36% of the total dose). Urinary metabolites were similar to those described for oral administration. Importantly, [14C]-equivalents were not detected in the blood at any time after dermal administration. These results indicate that the rate of MSK clearance is equivalent to its rate of absorption, and tissue exposure to intact MSK is expected to be limited.
Asunto(s)
Butanonas/farmacocinética , Administración Cutánea , Administración Oral , Animales , Disponibilidad Biológica , Femenino , Semivida , Inyecciones Intravenosas , Tasa de Depuración Metabólica , Ratones , Ratones EndogámicosRESUMEN
An assay was developed for the simultaneous measurement of cyclohexene oxide and its metabolites (cyclohexanol, trans-cyclohexane-1,2-diol, cyclohexane-1,2-diol-O-glucuronide, and N-acetyl-S-(2-hydroxycyclohexyl)-L-cysteine) in rat urine and plasma using gas chromatography. A mixture of ethyl acetate-acetonitrile (70:30) was used as the extracting solvent for both matrices. This liquid-liquid extraction procedure was followed by the separation of cyclohexene oxide and its metabolites on an HP-FFAP fused-silica capillary column. In order to determine the amount of cyclohexane-1,2-diol-O-glucuronide, samples were incubated at 37 degrees C with beta-glucuronidase and the amount of cyclohexane-1,2-diol formed from the reaction determined. The extraction efficiencies of cyclohexene oxide and cyclohexanol were greater than 90% both in urine and plasma. However, recovery from the plasma and urine for trans-cyclohexane-1,2-diol (60-68%) and N-acetyl-S-(2-hydroxycyclohexyl)-L-cysteine (approximately 76%) were considerably less. Long term stability studies showed that urine samples spiked with cyclohexene oxide and trans-cyclohexane-1,2-diol are stable at -20 degrees C for up to 9 weeks. However, plasma samples are only stable for up to 2 weeks under the same conditions. The calibration curves for all analytes were linear over the range of 12.5 to 400 micrograms/ml and correlation coefficients (r2) were greater than 0.990. The limit of detection for cyclohexene oxide, cyclohexanol, and N-acetyl-S-(2-hydroxycyclohexyl)-L-cysteine is 1.56 micrograms/ml, while the limit of detection for trans-cyclohexane-1,2-diol is 3.12 micrograms/ml. This method has been used for the determination of the disposition and metabolism of cyclohexene oxide, and may be applied in environmental monitoring, as well as in microbiological studies for other epoxide materials.
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Cromatografía de Gases/métodos , Ciclohexanos/análisis , Administración Oral , Animales , Ciclohexanos/administración & dosificación , Ciclohexanos/química , Ciclohexanos/metabolismo , Ciclohexenos , Modelos Lineales , Masculino , Concentración Osmolar , Ratas , Ratas Endogámicas F344 , Reproducibilidad de los Resultados , Sensibilidad y EspecificidadRESUMEN
The Kupffer cell inhibitor, gadolinium chloride (GdCl3), protects the liver from a number of toxicants that require biotransformation to elicit toxicity (i.e. 1,2-dichlorobenzene and CCl4), as well as compounds that do not (i.e. cadmium chloride and beryllium sulfate). The mechanism of this protection is thought to result from reduced secretion of inflammatory and cytotoxic products from Kupffer cells (KC). However, since other lanthanides have been shown to decrease cytochrome P450 (P450) activity, the following studies were designed to determine if GdCl3 pretreatment alters hepatic P450 levels or activity. The toxicological relevance of GdCl3-mediated alterations in P450 activity was also estimated by determining the effect of GdCl3 pretreatment on the susceptibility of primary cultured hepatocytes to CCl4 and cadmium chloride (CdCl2). Male and female Sprague-Dawley rats were given GdCl3 (i.v., 10 mg/kg). Twenty-four hours later, livers were either processed for preparation of microsomes or for primary cultures of hepatocytes. Gadolinium chloride treatment reduced total hepatic microsomal P450 as well as aniline hydroxylase activity by approximately 30% in males and 20% in females. In hepatocytes isolated from rats pretreated with GdCl3, the toxicity caused by CCl4, but not CdCl2 was reduced. Interestingly, when GdCl3 was administered in vitro to microsomes, there was no effect on either the microsomal P450 difference spectra or p-hydroxylation of aniline. However, when GdCl3 was incubated with isolated hepatocytes, the cytotoxicity of CCl4 (but not CdCl2) was partially attenuated. These results suggest that, in addition to its inhibitory effects on KC, GdCl3 produces other effects which may alter the susceptibility of hepatocytes to toxicity caused by certain chemicals.
Asunto(s)
Antiinflamatorios/farmacología , Tetracloruro de Carbono/toxicidad , Sistema Enzimático del Citocromo P-450/metabolismo , Gadolinio/farmacología , Macrófagos del Hígado/efectos de los fármacos , Hígado/efectos de los fármacos , Análisis de Varianza , Compuestos de Anilina/química , Compuestos de Anilina/metabolismo , Anilina Hidroxilasa/metabolismo , Animales , Antiinflamatorios/administración & dosificación , Biotransformación , Carcinógenos/química , Carcinógenos/metabolismo , Separación Celular , Células Cultivadas , Sistema Enzimático del Citocromo P-450/efectos de los fármacos , Femenino , Gadolinio/administración & dosificación , Hidroxilación , Inyecciones Intravenosas , Macrófagos del Hígado/citología , Macrófagos del Hígado/patología , Hígado/citología , Hígado/enzimología , Hígado/patología , Masculino , Microsomas Hepáticos/efectos de los fármacos , Microsomas Hepáticos/enzimología , Microsomas Hepáticos/patología , Ratas , Ratas Sprague-DawleyRESUMEN
Exposure of humans to toxic metals and metalloids is a major environmental problem. Many metals, such as cadmium, can be hepatotoxic. However, the mechanisms by which metals cause acute hepatic injury are in many cases unknown. Previous reports suggest a major role for inflammation in acute cadmium induced hepatotoxicity. In initial experiments we found that a non-hepatotoxic dose of cadmium chloride (CdCl2; 2.0 mg/kg, i.v.) markedly increased the clearance rate of colloidal carbon from the blood, which is indicative of enhanced phagocytic activity by Kupffer cells (resident hepatic macrophages). Thus. the objective these studies was to determine the involvement of Kupffer cells in cadmium induced liver injury by inhibiting their function with gadolinium chloride (GdCl3). Male Sprague-Dawley rats were administered GdCl3 (10 mg/kg, i.v.) followed 24 h later by a single dose of CdCl2 (3.0 and 4.0 mg/kg, i.v.). Twenty four hours after CdCl2 administration animals were killed and the degree of liver toxicity was assessed using plasma alanine aminotransferase (ALT), as well as light microscopy. Cadmium chloride administration produced multifocal hepatocellular necrosis and increased plasma ALT activity. Pretreatment with GdCl3 significantly reduced both the morphological changes and hepatic ALT release caused by CdCl2. However, the protection was specific to the liver, and did not alter CdCl2 induced testicular injury, as determined by histopathological damage. In many cases, the inducible cadmium-binding protein, metallothionein (MT) is often an essential aspect of the acquisition of cadmium tolerance in the liver. Although cadmium caused a dramatic induction of hepatic MT (32-fold), GdCl3 caused only a minor increase (2-fold). Combined CdCl2 and GdCl3 treatment did not induce levels to an extent greater than CdCl2 alone. As expected, GdCl3 also caused a slight increase in the amount of cadmium associated with the liver. In cultured hepatocytes isolated from GdCl3 pretreated rats, CdCl2 induced cytotoxicity was not significantly altered compared to control hepatocytes, indicating that the mechanism of tolerance required the presence of other cell types. Thus, GdCl3 attenuation of CdCl2 induced hepatotoxicity does not appear to be caused by increased tissue MT content or a decreased susceptibility of hepatocytes to cadmium. From these data, we concluded that tolerance to cadmium induced hepatotoxicity involves the inhibition of Kupffer cell function which results in a decreased inflammatory response and an altered progression of hepatic injury. These data further indicate that Kupffer cell function is critical to cadmium induced hepatocellular necrosis.
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Cloruro de Cadmio/toxicidad , Carcinógenos/toxicidad , Gadolinio/farmacología , Supresores de la Gota/farmacología , Macrófagos del Hígado/efectos de los fármacos , Hígado/efectos de los fármacos , Alanina Transaminasa/sangre , Animales , Cloruro de Cadmio/administración & dosificación , Células Cultivadas , Enfermedad Hepática Inducida por Sustancias y Drogas , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Gadolinio/administración & dosificación , Gadolinio/uso terapéutico , Supresores de la Gota/administración & dosificación , Inyecciones Intravenosas , Macrófagos del Hígado/citología , Macrófagos del Hígado/patología , Dosificación Letal Mediana , Hígado/citología , Hígado/patología , Hepatopatías/patología , Hepatopatías/prevención & control , Masculino , Metalotioneína/metabolismo , Necrosis , Fagocitosis/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Testículo/efectos de los fármacos , Testículo/patología , Distribución TisularRESUMEN
trans-Methyl styryl ketone (MSK; trans-4-phenyl-3-buten-2-one) is a beta-unsaturated ketone that has a wide range of uses in industry and is present in numerous consumer products. Although MSK has been shown to be positive in several in vitro mutagenic assays, it does not seem to be overtly toxic in animal models. This lack of toxicity may relate to its poor absorption and/or rapid elimination. However, little is known about the fate of MSK in the body. Studies were conducted to characterize the absorption, and disposition kinetics of MSK after intravenous, oral, and topical administration to male Fischer 344 rats. After intravenous administration of [14C]MSK (20 mg/kg, 120 microCi/kg), blood concentration-time data could be characterized with a biexponential equation and apparent first-order elimination kinetics. The following pharmacokinetic parameter values were obtained (mean +/- SD): terminal disposition half-life, 17.7 +/- 0.08 min; apparent steady-state volume of distribution, 0.89 +/- 0.14 liters/kg; systemic body clearance, 68.9 +/- 10.0 ml/kg *min; and mean residence time, 13.1 +/- 2.2 min. Within 48 hr, 95.5% of the dose was excreted in the urine and 2.7% in the feces. The major blood metabolite after intravenous administration was identified by GC/MS as the 4-phenyl-3-buten-2-ol (methyl styryl carbinol). After oral administration of [14C]MSK (200 mg/kg, 100 microCI/kg), approximately 96.6% of the dosed radioactivity was recovered in the urine and 4.8% in the faces within 48 hr. Major urinary metabolites identified by LC-MS/MS and quantified by HPLC radioassay were N-phenylacetyl-L-glycine (64.9% of dose) and N-benzyl-L-glycine (9.9% of dose). Parent compound could not be detected in the blood after oral administration, and 14C-equivalents in the blood never exceeded 1.3% of the dose. Results suggest near-total presystemic elimination of the oral dose. After topical application of [14C]MSK (250 mg/kg, 50 microCi/kg), > 60% of the dose was absorbed, and the majority of the dose was excreted into the urine (55% of dose) in the form of metabolites. Urinary metabolites were similar to those described after oral administration. 14C-equivalents were not detected in the blood at any time after topical administration. These results indicate that MSK is almost totally metabolized before systemic distribution after oral or topical administration. The systemic exposure dose of MSK seems to be exceedingly low at the doses studied herein.
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Butanonas/farmacocinética , Administración Oral , Administración Tópica , Animales , Butanonas/administración & dosificación , Heces/química , Cromatografía de Gases y Espectrometría de Masas , Inyecciones Intravenosas , Masculino , Ratas , Ratas Endogámicas F344RESUMEN
Previous studies have shown that large doses of vitamin A potentiate chemical-induced liver injury and that the Kupffer cell is directly involved in this potentiation. Therefore, these studies were designed to determine if Kupffer cells isolated from vitamin A treated male Sprague-Dawley rats (75 mg/kg/day for 3-7 days as all- trans-retinol) had altered activity and function. Respiratory activity of Kupffer cells isolated from rats treated with vitamin A for 3 to 7 days markedly increased. Similarly, phagocytic activity was significantly elevated (up to 9-fold) after exposure to vitamin A for 3 to 7 days. Production of reactive oxygen species, measured by luminol-enhanced chemiluminescence of Kupffer cells isolated after 7 days of vitamin A exposure, was significantly higher than that of control cells when stimulated with opsonized zymosan. Also, the release of superoxide anion by individual Kupffer cells isolated from vitamin A treated rats was nearly three times greater than that of control cells. Basal production of tumor necrosis factor-alpha (TNF-alpha) and prostaglandin E2 (PGE2) production were significantly elevated in Kupffer cells isolated from rats treated with vitamin A. Lastly, peripheral blood monocytes (PBMC) isolated from rats treated with vitamin A for 7 days had a significantly greater respiratory activity, as well as TNF-alpha and PGE2 production, than PBMC isolated from control rats. Our data suggest that large doses of vitamin A enhance both Kupffer cell and PBMC function. Upregulation of the activity by these phagocytic cells may play a role in the vitamin A potentiation of chemical-induced liver injury.
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Macrófagos del Hígado/metabolismo , Monocitos/metabolismo , Vitamina A/farmacología , Animales , Células Cultivadas , Dinoprostona/biosíntesis , Macrófagos del Hígado/citología , Macrófagos del Hígado/efectos de los fármacos , Mediciones Luminiscentes , Masculino , Monocitos/citología , Monocitos/efectos de los fármacos , Fagocitosis/fisiología , Ratas , Ratas Sprague-Dawley , Especies Reactivas de Oxígeno , Superóxidos/metabolismo , Factor de Necrosis Tumoral alfa/biosíntesisRESUMEN
Cyclohexene oxide (CHO) is a monomer intermediate used in the synthesis of pesticides, pharmaceuticals, and perfumes. Although CHO has a variety of industrial uses where direct human exposure is possible, very little is known about its fate in the body. Therefore, the objectives of this study were to determine the absorption, distribution, metabolism, and excretion of cyclohexene oxide after oral, intravenous, and dermal exposure in male Fischer 344 rats and female B6C3F, mice. After intravenous administration of [14C]CHO (50 mg/kg), CHO was rapidly distributed, metabolized, and excreted into the urine. Plasma concentrations of CHO rapidly declined and were below the limit of detection within 60 min. Average (+/- SD) values for terminal disposition half-life, apparent volume of distribution at steady-state, and systemic body clearance were: 19.3 +/- 1.6 min; 0.44 +/- 0.08 liter/kg; and 31.3 +/- 0.5 ml/kg * min, respectively. After oral administration of [14C]CHO (10 and 100 mg/kg), it was found that 14C-equivalents were rapidly excreted in the urine of both species. At 48 hr, the majority of the dose (73-93%) was recovered in urine, whereas fecal elimination accounted for only 2-5% of the dose. At no time after oral administration was parent CHO detected in the blood. However, its primary metabolite cyclohexane-1,2-diol was present for different lengths of time depending on the dose. Four metabolites were detected and identified in mouse urine by MS: cyclohexane-1,2-diol; cyclohexane-1,2-diol-O-glucuronide; N-acetyl-S-(2-hydroxycyclohexyl)-L-cysteine; and cyclohexane-1,2-diol-O-sulfate. The sulfate conjugate was not present in rat urine. Topical application of [14C]CHO (60 mg/kg) provided poor absorption in both species. The majority of 14C-equivalents applied dermally were recovered from the charcoal skin trap (approximately 90% of the dose). Only 4% of the dose was absorbed, and the major route of elimination was via the urine. To evaluate the toxicity of CHO, animals were given daily doses of CHO orally and topically for 28 days. No statistically significant changes in final body weights or relative organ weights were noted in rats or mice treated orally with CHO up to 100 mg/kg or up to 60 mg/kg when given topically. Very few lesions were found at necropsy, and none were considered compound related. In conclusion, regardless of route, CHO is rapidly eliminated and excreted into the urine. Furthermore, after either oral or dermal administration, it is unlikely that CHO reaches the systemic circulation intact due to its rapid metabolism, and is therefore unable to cause toxicity in the whole animal under the test conditions used in this study.
Asunto(s)
Ciclohexanos/metabolismo , Ciclohexanos/farmacocinética , Administración Cutánea , Administración Oral , Animales , Cromatografía Líquida de Alta Presión , Ciclohexanos/toxicidad , Ciclohexenos , Estabilidad de Medicamentos , Femenino , Concentración de Iones de Hidrógeno , Inyecciones Intravenosas , Masculino , Ratones , Ratones Endogámicos , Ratas , Ratas Endogámicas F344RESUMEN
Recently, it has been shown that large doses of all-trans-retinol (vitamin A) can potentiate the hepatotoxicity of several organic chemicals in the rat. Whether retinol pretreatment can alter the acute hepatotoxicity of an inorganic chemical, such as cadmium, is unknown. Therefore, the objective of this study was to determine how retinol might affect the acute toxicity of cadmium chloride (CdCl2) and to elucidate possible mechanisms. Cadmium exposure can induce acute, lethal hepatocellular necrosis in rodents, as well as lesions in the lung, kidney, testis, and gastrointestinal tract. In the present studies, male Sprague-Dawley rats were pretreated with retinol (75 mg/kg/day, po) for 7 consecutive days. One day after the last dose of retinol, animals were given a single injection of CdCl2 (2.5 to 4.0 mg/kg, iv). Cadmium chloride administration to unpretreated control rats caused extensive hepatic, renal, pulmonary, and testicular toxicity at 6, 24, and 48 hr postdosing as evaluated by plasma enzymes and/or histopathology. In retinol-pretreated rats, a significant attenuation of CdCl2-induced tissue injury was observed. Since the inducible cadmium-binding protein metallothionein (MT) is often an essential aspect of cadmium tolerance, its content in tissue was assessed using the cadmium-hemoglobin assay. Interestingly, retinol pretreatment significantly increased MT in the liver by sevenfold, but had no effect on lung, kidney, testicular, or pancreatic MT content. Although this increase in hepatic MT was much less than that induced by CdCl2, it was additive to the induction of CdCl2. Furthermore, the tissue distribution of cadmium was significantly altered by retinol pretreatment. The liver accumulated more cadmium, while less cadmium was found in the lung, kidney, and testis in retinol-pretreated rats than in controls. In monolayers of primary isolated hepatocytes, CdCl2-induced toxicity was significantly reduced in cells isolated from retinol-pretreated rats compared to those isolated from control rats. The dose response was shifted to the right and the in vitro cadmium LC50 was increased by in vivo retinol exposure from 1.1 +/- 0.1 to 2.4 +/- 0.04 microM. From these data it is concluded that the induction of hepatic MT is an essential aspect of retinol-induced tolerance to CdCl2 hepatotoxicity, as well as toxicity in other tissues.
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Hepatopatías/prevención & control , Hígado/efectos de los fármacos , Metalotioneína/biosíntesis , Vitamina A/administración & dosificación , Animales , Cadmio/análisis , Cloruro de Cadmio/farmacocinética , Células Cultivadas/efectos de los fármacos , Enfermedad Hepática Inducida por Sustancias y Drogas , Esquema de Medicación , Tolerancia a Medicamentos , Inyecciones Intravenosas , L-Lactato Deshidrogenasa/efectos de los fármacos , L-Lactato Deshidrogenasa/metabolismo , Hígado/química , Hígado/patología , Hepatopatías/patología , Masculino , Metalotioneína/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Testículo/efectos de los fármacos , Testículo/patología , Distribución TisularRESUMEN
1-Nitronaphthalene is a mutagenic particulate of diesel exhaust which causes acute liver and lung toxicity in rodents. The studies presented here describe morphological changes in the lung and liver at several time intervals following a single injection of 1-nitronaphthalene (100 mg/kg, i.p.) in male Sprague-Dawley rats using transmission and scanning electron microscopy. Although both the lungs and liver are injured by 1-nitronaphthalene, the lungs appear to be the primary target organ. Within 4 h of treatment, all 1-nitronaphthalene treated animals exhibited respiratory distress characterized by labored breathing, severe gasping and chromodacryorrhea. The primary ultrastructural alteration were hydropic changes in the non-ciliated bronchiolar (Clara) cells of the distal-most bronchioles of the lung. These were apparent as early as 1 h after 1-nitronaphthalene injection, while adjacent ciliated cells showed no alterations. Over a 24 h period, the bronchioles showed progressive ultrastructural changes leading to necrosis and exfoliation of both ciliated and Clara cells. Interstitial pneumonitis and edema were observed in all animals treated with 1-nitronaphthalene, and was usually associated with bronchioles containing necrotic epithelium. In the liver, ultrastructural changes were observed in the centrilobular hepatocytes at 8 h and consisted of cytomegaly, loss of continuous inner membrane and reduced matrix density of the mitochondria. At 48 h, cellular damage to centrilobular hepatocytes was severe and nearly all mitochondria were damaged. Elevated levels of alanine aminotransferase, aspartate aminotransferase and bilirubin were detected in the serum of animals treated with 1-nitronaphthalene at 8-48 h. In conclusion, 1-nitronaphthalene is a pulmonary toxicant with a unique progression of injury, which primarily damages Clara cells followed by ciliated cells. This disparity is likely due to a difference in the bioactivation of 1-nitronaphthalene. Furthermore, this systemic toxicant also has injurious effects on the centrilobular region of the liver which precedes lung injury.
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Carcinógenos/toxicidad , Hígado/efectos de los fármacos , Hígado/ultraestructura , Pulmón/efectos de los fármacos , Pulmón/ultraestructura , Naftalenos/toxicidad , Animales , Análisis Químico de la Sangre , Hígado/patología , Pulmón/patología , Masculino , Ratas , Ratas Sprague-DawleyAsunto(s)
Enfermedad Hepática Inducida por Sustancias y Drogas , Interacciones Farmacológicas , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/etiología , Animales , Tetracloruro de Carbono/farmacología , Tetracloruro de Carbono/toxicidad , Clorobencenos/antagonistas & inhibidores , Clorobencenos/toxicidad , Antagonismo de Drogas , Sinergismo Farmacológico , Humanos , Naftalenos/efectos adversos , Naftalenos/toxicidad , Fenobarbital/efectos adversosRESUMEN
Evidence suggests that 7 days of retinol pretreatment potentiates chemical-induced liver injury by a mechanism that involves activation of Kupffer cells (KC). These studies were designed to determine if shorter dosing regimens of retinol potentiate carbon tetrachloride (CCl4). Initially, a single dose of retinol was shown to potentiate the hepatotoxicity of CCl4. Male Sprague-Dawley rats were pretreated with all-trans-retinol (75 mg/kg p.o.) 24 hr prior to KC isolation or administration of CCl4 (0.2 ml/kg i.p.). KC isolated at 24 hr after retinol released increased amounts of superoxide anion when stimulated with zymosan or phorbol myristate acetate. At 24 hr after CCl4, plasma ALT activities and histological sections of liver were examined. Retinol-pretreated rats showed a significant elevation in both enzyme leakage and centrilobular to midzonal necrosis compared to retinol vehicle controls following CCl4. Although complete protection was not seen, depletion of KC or neutrophils (PMNs) (by gadolinium chloride (GdCl3) or a PMN-depleting antibody, respectively) significantly reduced the hepatotoxicity of 1 day retinol/CCl4 liver injury. Immunohistochemical analysis of livers showed significant elevations in positive staining for ED2, ED1, and HIS48 in retinol-pretreated rats given CCl4. GdCl3 effectively reduced ED2 staining but did not greatly affect HIS48 staining. Additional studies were performed to estimate the effect of retinol on noninflammatory processes. While total cytochrome P450 was not increased, the activity and concentration of CYP2E1 were both significantly elevated after a single dose of retinol. Hepatocytes isolated from 1-day retinol-treated rats were also more susceptible to CCl4 injury, a consequence that is most likely related to elevated CYP2E1 activity. These findings suggest that a single pretreatment with retinol may potentiate CCl4 hepatotoxicity by multiple mechanisms which involve increased biotransformation and inflammatory cell activities.
Asunto(s)
Tetracloruro de Carbono/toxicidad , Sistema Enzimático del Citocromo P-450/fisiología , Macrófagos del Hígado/fisiología , Hígado/efectos de los fármacos , Neutrófilos/fisiología , Vitamina A/farmacología , Animales , Citocromo P-450 CYP2E1/fisiología , Gadolinio/farmacología , Masculino , Ratas , Ratas Sprague-DawleyRESUMEN
We have previously shown that retinol pretreatment limits the amount of pulmonary injury caused by 1-nitronaphthalene in male Sprague-Dawley rats. The main objective of this study was to determine if retinol pretreatment can protect the lung from the toxicity of other systemic pneumotoxicants. Furthermore because retinol has been shown to alter the hepatotoxicity of several chemicals, a secondary objective was to evaluate its effects on the liver injury caused by these toxicants. Rats were pretreated with all-trans-retinol (75 mg/kg/day, p.o.) for 1 week, and given 2-nitronaphthalene (200 mg/kg, i.p.) or paraquat (25 mg/kg, i.p.). At 24 h after 2-nitronaphthalene treatment, pulmonary morphological changes associated with the bronchiolar epithelium, as well as a moderate pneumonitis were observed. Pretreatment of rats with retinol inhibited the majority of 2-nitronaphthalene-induced pulmonary damage including the infiltration of inflammatory cells and associated edema. However, these animals possessed limited lesions associated with their non-ciliated bronchiolar epithelial (Clara) cells. Interestingly, pretreatment with retinol also caused a significant potentiation of 2-nitronaphthalene-induced liver damage. The potentiated hepatotoxicity consisted of centrilobular hepatocyte necrosis with infiltration of inflammatory cells. Gadolinium chloride (GdCl3), an inhibitor of Kupffer cell function, significantly decreased the potentiated hepatocellular injury. In paraquat-treated rats focal areas of damage to the alveolar parenchyma, consisting of inflammatory cell infiltration and alveolar sac remodeling, were observed at 48 h. Pretreatment with retinol caused significant protection from the pulmonary damaged caused by paraquat. Specifically, there was a lack of alveolar parenchymal cell damage and inflammatory cell infiltration in these animals. From these experiments, we conclude that retinol pretreatment decreases the severity of 2-nitronaphthalene and paraquat-induced pulmonary toxicity, apparently by inhibiting the inflammatory responses associated with the progression of toxic injury. In the liver, retinol potentiated 2-nitronaphthalene-induced hepatotoxicity by a mechanism which directly involves Kupffer cells.
Asunto(s)
Enfermedad Hepática Inducida por Sustancias y Drogas , Enfermedades Pulmonares/inducido químicamente , Vitamina A/farmacología , Animales , Tetracloruro de Carbono/toxicidad , Sinergismo Farmacológico , Gadolinio/farmacología , Hígado/efectos de los fármacos , Hígado/patología , Hepatopatías/prevención & control , Pulmón/efectos de los fármacos , Pulmón/patología , Enfermedades Pulmonares/prevención & control , Masculino , Naftalenos/toxicidad , Paraquat/toxicidad , Ratas , Ratas Sprague-DawleyRESUMEN
Large doses of retinol (vitamin A) have been shown to potentiate the hepatotoxicity of several chemicals in rats. The objective of this study was to determine how retinol would affect the pulmonary and hepatic toxicity caused by 1-nitronaphthalene (1-NN). All-trans-retinol (75 mg/kg/day, po) was administered for 7 days to male Sprague-Dawley rats. One day after the last dose of retinol, animals were given a single injection of 1-NN (100 mg/kg, ip). At 24 hr, animals receiving retinol vehicle and 1-NN exhibited respiratory distress syndrome and chromodacryorrhea. Pulmonary morphological changes included necrosis and exfoliation of the bronchiolar epithelium, as well as infiltration of inflammatory cells into the interstitial areas around affected bronchioles. The bronchioalveolar lavage fluid from these animals exhibited significant increases in the activities of gamma-glutamyl transpeptidase (GGT), lactate dehydrogenase (LDH), as well as protein and inflammatory cell content. Following pretreatment with retinol, none of the animals treated with 1-NN exhibited outward signs of toxicity. In addition, the lavage fluid of these rats revealed significant reductions in inflammatory cells, protein, and LDH activity. However, lavage fluid GGT activity was significantly increased. Morphological evaluation of the lungs revealed nonciliated bronchiolar epithelial (Clara) cell damage with no associated inflammation. Retinol pretreatment resulted in potentiated hepatotoxicity as indicated by increases in plasma alanine aminotransferase and GGT activities, as well as plasma total bilirubin. The altered plasma enzyme activities correlated with increased hepatocyte and bile duct epithelial necrosis, as well as an increased infiltration of neutrophils into the areas around bile ducts. Retinol potentiation of 1-NN-induced hepatocyte necrosis was significantly reduced following pretreatment with gadolinium chloride (GdCl3). From these experiments, we conclude that in the lung pretreatment with retinol decreased the severity of 1-NN-induced toxicity apparently by an anti-inflammatory mechanism. In the liver, retinol potentiated 1-NN-induced liver injury apparently through a proinflammatory mechanism by activating Kupffer cells and increasing the infiltration of neutrophils into the periportal regions adjacent to bile ducts.