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1.
Ther Drug Monit ; 2023 Nov 27.
Artículo en Inglés | MEDLINE | ID: mdl-38018864

RESUMEN

BACKGROUND: Thiamylal exerts excellent sedative effects. However, it is not routinely used because of its serious adverse effects. This study aimed to clarify the target blood concentration range and infusion rate of thiamylal in children by measuring its blood concentration and evaluating its relationship with efficacy and adverse effects. METHODS: This study was approved by the Ethics Committee of Japanese Red Cross Kumamoto Hospital. The authors included 10 children aged between 1 and 7 years who had received continuous intravenous (IV) infusion of thiamylal for the management of refractory status epilepticus, excluding those who met the exclusion criteria. After a 2 mg/kg bolus injection of thiamylal, continuous IV infusion was initiated at a rate of 2-3 mg/kg/h. Thiamylal concentration in the blood was measured using high-performance liquid chromatography. The State Behavioral Scale and the frequency of bolus injections were used to evaluate efficacy. Blood pressure and heart rate were measured to evaluate adverse effects. Statistical analyses of the time to awakening and the factors affecting it were also conducted. RESULTS: The State Behavioral Scale score during thiamylal administration was -2 or lower in all cases, suggesting that the depth of sedation was sufficient. The frequency of bolus injections decreased in a blood concentration-dependent manner, suggesting that the frequency tended to decrease, especially at thiamylal blood concentrations of 20 mcg/mL or higher. An increase of the infusion rate to 3 mg/kg/h was recommended, because the blood concentration may not reach 20 mcg/mL at an infusion rate of 2 mg/kg/h. There was also a case in which a rapid increase in blood concentration accompanied by a decrease in blood pressure and heart rate was observed when the infusion rate was increased to 4 mg/kg/h. Furthermore, the time to awakening after the end of administration correlated with the highest blood concentration during administration; therefore, delayed awakening was noted when using a high dose of thiamylal. CONCLUSIONS: The target blood concentration of thiamylal in children should be 20-30 mcg/mL, and the infusion rate should be based on 3 mg/kg/h.

2.
ACS Omega ; 7(34): 29944-29951, 2022 Aug 30.
Artículo en Inglés | MEDLINE | ID: mdl-36061730

RESUMEN

Aripiprazole (ARP), an antipsychotic drug, binds more strongly to human serum albumin (HSA) than the other ARP derivatives. In addition, the signs for the extrinsic Cotton effects for HSA complexed with ARP or deschloro-ARP are reversed. In this study, we report on a structural-chemical approach using circular dichroism (CD) spectroscopic analysis, X-ray crystallographic analysis, and molecular dynamics simulations. The objective was to examine the relationship between the induced CD spectra and the structural features of the HSA complexes with ARP or deschloro-ARP. The intensity of the induced CD spectra of the HSA complexes with ARP or deschloro-ARP was reduced with increasing temperature. We determined the crystal structure of the HSA complexed with deschloro-ARP in this study and compared it to HSA complexed with ARP that we reported previously. The comparison of these structures revealed that both ARP and deschloro-ARP were bound at the site II pocket in HSA and that the orientation of the molecules was nearly identical. Molecular dynamics simulations indicated that the molecular motions of ARP and deschloro-ARP within the site II pocket were different from one another and the proportion of stacking interaction formations of Tyr411 with the dihydroquinoline rings of ARP and deschloro-ARP was also different. These findings indicate that the induced CD spectra are related to the molecular motions and dynamic interactions of ARP and deschloro-ARP in HSA and may help to understand the molecular recognition and motion that occurs within the binding site for the other HSA ligands more clearly.

3.
Ther Drug Monit ; 44(5): 633-640, 2022 10 01.
Artículo en Inglés | MEDLINE | ID: mdl-35383726

RESUMEN

BACKGROUND: Rigorous dose adjustment by therapeutic drug monitoring (TDM) is recommended when everolimus (EVR) is administered for immunosuppression. In this study, the authors developed a highly sensitive ultrahigh-performance liquid chromatography coupled with the tandem mass spectrometry (UHPLC-MS/MS) method for measuring EVR concentrations in whole blood using a high-throughput solid-phase extraction method for sample pretreatment. Furthermore, the blood EVR concentrations in routine TDM samples from patients who underwent renal transplantation measured using the established UHPLC-MS/MS method were compared with those measured using the latex agglutination turbidimetric immunoassay (LTIA). METHODS: Blood samples were pretreated by solid-phase extraction using a 96-well HLB µElution plate. The clinical application of the newly developed method was evaluated using 87 blood samples from 19 patients who underwent kidney transplant. RESULTS: The calibration curve showed good linearity over a wide range of 0.1-50 ng/mL, with relative error ≤15% obtained from the back calculation of calibrators, and ≤20% for the lower limit of quantification. Within-batch and batch-to-batch accuracies and precisions fulfilled the acceptance criteria of the US Food and Drug Administration guidelines for bioanalytical method validation. The extraction recovery rates were good (≥65.2%), and almost no matrix effects were found in any of the quality control samples. Blood EVR concentrations measured by UHPLC-MS/MS were positively correlated with those measured by LTIA. A Bland-Altman plot indicated that the UHPLC-MS/MS method yielded better measurements than the LTIA method, regardless of the concentration. CONCLUSIONS: Therefore, the authors succeeded in developing a novel high-sensitivity and high-throughput method for measuring blood EVR concentration by UHPLC-MS/MS using a µElution plate for sample pretreatment.


Asunto(s)
Everolimus , Espectrometría de Masas en Tándem , Cromatografía Líquida de Alta Presión/métodos , Cromatografía Liquida , Monitoreo de Drogas/métodos , Humanos , Espectrometría de Masas en Tándem/métodos
4.
ACS Omega ; 7(5): 4413-4419, 2022 Feb 08.
Artículo en Inglés | MEDLINE | ID: mdl-35155934

RESUMEN

The effects of myristate on the induced circular dichroism spectra of aripiprazole (ARP) bound to human serum albumin (HSA) were investigated. High concentrations of myristate reversed the Cotton effects induced in the ARP-HSA system. The observed ellipticities increased with increasing drug concentration up to an ARP-to-HSA molar ratio of 1:1 and then decreased, indicating that the extrinsic Cotton effects were generated by the binding of ARP molecules to the high- and low-affinity sites in HSA. The data for the concentration of free ARP show that myristate displaces ARP molecules from HSA. Moreover, the free fractions of ARP in the ARP-HSA-myristate system increased significantly when adding fusidic acid, a subdomain IB ligand. In the crystal structure of the ARP-HSA-myristate ternary complex, one ARP molecule is bound to subdomain IB, and the interaction between the carbonyl group of ARP and the aromatic ring of Tyr138 in subdomain IB is essential for binding to occur. Meanwhile, the ARP molecule in the ARP-HSA binary complex structure is bound only to subdomain IIIA. Consequently, the inversion in the extrinsic Cotton effects in the ARP-HSA system can be attributed to the modification of the geometry within the binding pocket, in addition to the transfer of ARP from subdomain IIIA to subdomain IB through the displacement as a result of the binding of myristate to subdomain IIIA.

6.
Toxins (Basel) ; 13(11)2021 11 18.
Artículo en Inglés | MEDLINE | ID: mdl-34822595

RESUMEN

The binding of drugs to plasma protein is frequently altered in certain types of renal diseases. We recently reported on the effects of oxidation and uremic toxins on the binding of aripiprazole (ARP) to human serum albumin. In our continuing investigations, we examined the binding of ARP to plasma pooled from patients with chronic renal dysfunction. We examined the issue of the molecular basis for which factors affect the changes in drug binding that accompany renal failure. The study was based on the statistical relationships between ARP albumin binding and biochemical parameters such as the concentrations of oxidized albumin and uremic toxins. The binding of ARP to plasma from chronic renal patients was significantly lower than healthy volunteers. A rational relationship between the ARP binding rate and the concentration of toxins, including indoxyl sulphate (IS) and p-cresyl sulphate (PCS), was found, particularly for IS. Moreover, multiple regression analyses that involved taking other parameters such as PCS or oxidized albumin ratio to IS into account supports the above hypothesis. In conclusion, the limited data reported in this present study indicates that monitoring IS in the blood is a very important determinant in the dosage plan for the administration of site II drugs such as ARP, if the efficacy of the drug in renal disease is to be considered.


Asunto(s)
Antipsicóticos/metabolismo , Aripiprazol/metabolismo , Proteínas Sanguíneas/metabolismo , Fallo Renal Crónico/sangre , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Cresoles/metabolismo , Femenino , Humanos , Indicán/metabolismo , Masculino , Unión Proteica , Estudios Retrospectivos , Albúmina Sérica Humana/metabolismo , Ésteres del Ácido Sulfúrico/metabolismo , Adulto Joven
7.
Clin Transl Sci ; 14(5): 2034-2042, 2021 09.
Artículo en Inglés | MEDLINE | ID: mdl-34058078

RESUMEN

Because tacrolimus is predominantly metabolized by CYP3A, the blood concentration/dose (C/D) ratio is affected by CYP3A5 polymorphism. Parathyroid hormone (PTH) expression increases in secondary hyperparathyroidism, which is frequently associated with end-stage renal disease. Recently, PTH has been shown to downregulate CYP3A expression at mRNA level. In this study, we examined the influence of CYP3A5 polymorphism on and association of serum intact-PTH (iPTH) level with blood tacrolimus concentration in patients with end-stage renal disease just before kidney transplantation. Forty-eight patients who satisfied the selection criteria were analyzed. Subjects were classified into two phenotype subgroups: CYP3A5 expressor (CYP3A5*1/*1 and *1/*3; n = 15) and CYP3A5 nonexpressor (CYP3A5*3/*3; n = 33). The blood tacrolimus C/D (per body weight) ratio was significantly lower in CYP3A5 expressors than that in CYP3A5 nonexpressors. A significant positive correlation was found between tacrolimus C/D and iPTH concentrations (r = 0.305, p = 0.035), and the correlation coefficient was higher after excluding 20 patients co-administered CYP3A inhibitor or inducer (r = 0.428, p = 0.023). A multiple logistic regression analysis by stepwise selection identified CYP3A5 polymorphism and serum iPTH level as significant factors associated with tacrolimus C/D. These results may suggest the importance of dose design considering not only the CYP3A5 phenotype but also serum iPTH level when using tacrolimus in patients who undergo renal transplantation.


Asunto(s)
Citocromo P-450 CYP3A/genética , Rechazo de Injerto/prevención & control , Fallo Renal Crónico/terapia , Trasplante de Riñón/efectos adversos , Tacrolimus/farmacocinética , Adulto , Citocromo P-450 CYP3A/metabolismo , Relación Dosis-Respuesta a Droga , Femenino , Rechazo de Injerto/inmunología , Humanos , Hiperparatiroidismo Secundario/sangre , Hiperparatiroidismo Secundario/etiología , Hiperparatiroidismo Secundario/metabolismo , Fallo Renal Crónico/sangre , Fallo Renal Crónico/complicaciones , Masculino , Persona de Mediana Edad , Hormona Paratiroidea/sangre , Hormona Paratiroidea/metabolismo , Variantes Farmacogenómicas , Polimorfismo de Nucleótido Simple , Estudios Retrospectivos , Tacrolimus/administración & dosificación
8.
Biol Pharm Bull ; 43(10): 1583-1590, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32999168

RESUMEN

Chronic kidney disease (CKD) patients with secondary hyperparathyroidism (SHPT) have an increased risk of cardiovascular disease (CVD). Cinacalcet is a calcimimetic that permits impaired endothelial functions to be recovered via inhibiting parathyroid hormone (PTH) production in SHPT patients. However, the underlying mechanism for its action remains unknown. The purpose of this study was to examine the effect of cinacalcet on the redox state of human serum albumin (HSA), a reliable marker for assessing endothelial oxidative damage in SHPT patients who were receiving hemodialysis. Cinacalcet was administered to six SHPT patients for a period of 8 weeks. After 4 weeks of treatment, cinacalcet significantly decreased the oxidized albumin ratio which is a ratio of reduced and oxidized forms of HSA via increasing reduced form of HSA. Moreover, the radical scavenging abilities of HSA that was isolated from SHPT patients were increased by cinacalcet, suggesting the recovery of the impaired vascular anti-oxidant ability. Interestingly, the oxidized albumin ratio in SHPT patients was significantly higher than that in hemodialysis patients. In addition, the changes of intact PTH levels were significantly correlated with the oxidized albumin ratio. It therefore appears that PTH may induce oxidative stress in SHPT patients. In fact, an active analogue of PTH increased the production of reactive oxygen species in human endothelial cells. Thus, cinacalcet exhibits anti-oxidative activity through its pharmacological action. Additionally, cinacalcet itself showed radical scavenging activity. In conclusion, cinacalcet improves the redox status of HSA by inhibiting PTH production and partially by its radical scavenging action.


Asunto(s)
Antioxidantes/uso terapéutico , Cinacalcet/uso terapéutico , Hiperparatiroidismo Secundario/sangre , Hiperparatiroidismo Secundario/tratamiento farmacológico , Diálisis Renal/tendencias , Albúmina Sérica Humana/metabolismo , Adulto , Anciano , Antioxidantes/farmacología , Hormonas y Agentes Reguladores de Calcio/farmacología , Hormonas y Agentes Reguladores de Calcio/uso terapéutico , Cinacalcet/farmacología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Oxidación-Reducción/efectos de los fármacos , Hormona Paratiroidea/antagonistas & inhibidores , Hormona Paratiroidea/sangre , Diálisis Renal/efectos adversos , Resultado del Tratamiento
9.
Biol Pharm Bull ; 42(5): 786-791, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31061321

RESUMEN

The mechanism responsible for the decreased extra-renal CYP3A activity in chronic kidney disease (CKD) patients remains unknown. Using an animal model, we previously found that elevated levels of serum intact parathyroid hormone (iPTH) caused a reduced CYP3A activity. This retrospective observational study assessed the relationship between serum iPTH levels and the blood concentration or dosage of tacrolimus, a CYP3A substrate, after oral administration in kidney transplant patients. Thirty-four patients were enrolled who had kidney transplants between April 2014 and March 2016 and who had been administrated once- daily prolonged-release tacrolimus (Graceptor®, Astellas Pharm Inc.). Among the 34 patients, 22 had taken a CYP3A inhibitor. These patients were excluded from the study. A significant positive correlation between serum iPTH and tacrolimus trough levels was found at 4 d before kidney transplantation in 12 patients who were not receiving potent CYP3A inhibitor. In addition, serum iPTH levels before transplantation could serve as a factor for the dose of tacrolimus up to 1 year after transplantation. Monitoring serum iPTH levels could predict the trough level for the initial administration of tacrolimus, and may serve as an index for the initial dose of tacrolimus in kidney transplantation patients.


Asunto(s)
Inmunosupresores/administración & dosificación , Trasplante de Riñón , Hormona Paratiroidea/sangre , Tacrolimus/administración & dosificación , Adulto , Biomarcadores/sangre , Esquema de Medicación , Femenino , Humanos , Inmunosupresores/farmacocinética , Masculino , Persona de Mediana Edad , Tacrolimus/farmacocinética , Adulto Joven
10.
Biochem Pharmacol ; 145: 192-201, 2017 12 01.
Artículo en Inglés | MEDLINE | ID: mdl-28843775

RESUMEN

Chronic kidney disease (CKD), which affects, not only renal clearance, but also non-renal clearance, is accompanied by a decline in renal function. Although it has been suggested that humoral factors, such as uremic toxins that accumulate in the body under CKD conditions, could be involved in the changes associated with non-renal drug clearance, the overall process is not completely understood. In this study, we report on the role of parathyroid hormone (PTH), a middle molecule uremic toxin, on the expression of drug metabolizing or transporting proteins using rats with secondary hyperparathyroidism (SHPT) as models. In SHPT rats, hepatic and intestinal CYP3A expression was suppressed, but the changes were recovered by the administration of the calcimimetic cinacalcet, a PTH suppressor. Under the same experimental conditions, a pharmacokinetic study using orally administered midazolam, a substrate for CYP3A, showed that the AUC was increased by 5 times in SHPT rats, but that was partially recovered by a cinacalcet treatment. This was directly tested in rat primary hepatocytes and intestinal Caco-2 cells where the expression of the CYP3A protein was down-regulated by PTH (1-34). In Caco-2 cells, PTH (1-34) down-regulated the expression of CYP3A mRNA, but an inactive PTH derivative (13-34) had no effect. 8-Bromo-cyclic adenosine monophosphate, a membrane-permeable cAMP analog, reduced mRNA expression of CYP3A whereas the inhibitors of PI3K, NF-κB, PKC and PKA reversed the PTH-induced CYP3A down-regulation. These results suggest that PTH down-regulates CYP3A through multiple signaling pathways, including the PI3K/PKC/PKA/NF-κB pathway after the elevation of intracellular cAMP, and the effect of PTH can be prevented by cinacalcet treatment.


Asunto(s)
AMP Cíclico/metabolismo , Citocromo P-450 CYP3A/metabolismo , Regulación hacia Abajo/fisiología , Hormona Paratiroidea/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Proteína Quinasa C/metabolismo , Animales , Células CACO-2 , Cinacalcet/toxicidad , AMP Cíclico/genética , Citocromo P-450 CYP3A/genética , Moduladores del GABA/farmacocinética , Regulación Enzimológica de la Expresión Génica/fisiología , Hepatocitos/efectos de los fármacos , Hepatocitos/metabolismo , Humanos , Hiperparatiroidismo/inducido químicamente , Hiperparatiroidismo/metabolismo , Masculino , Midazolam/farmacocinética , FN-kappa B/genética , FN-kappa B/metabolismo , Fosfatidilinositol 3-Quinasas/genética , Proteína Quinasa C/genética , Distribución Aleatoria , Ratas , Insuficiencia Renal Crónica/metabolismo , Transducción de Señal
11.
J Pharmacol Exp Ther ; 352(2): 244-57, 2015 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-25398242

RESUMEN

Since reactive oxygen species (ROS) derived from Kupffer cells (KC), especially CD68(+) KC, play a key role in the induction of hepatic oxidative stress and injuries, we developed a polythiolated- and mannosylated human serum albumin (SH-Man-HSA), which functions as a novel nanoantioxidant for delivering thiol to CD68(+) KC. In vitro electron paramagnetic resonance coupled with pharmacokinetics and immunohistochemical studies showed that SH-Man-HSA possessed powerful radical-scavenging activity and rapidly and selectively delivered thiols to the liver via mannose receptor (CD206) on CD68(+) cells. SH-Man-HSA significantly improved the survival rate of concanavalin-A (Con-A)-treated mice. Moreover, SH-Man-HSA exhibited excellent hepatoprotective functions, not by decreasing tumor necrosis factor or interferon-γ production that is closely associated with Con-A-induced hepatitis, but by suppressing ROS production. Interestingly, the protective effect of SH-Man-HSA was superior to N-acetyl cysteine (NAC). This could be attributed to the difference in the inhibition of hepatic oxidative stress between the two antioxidants depending on their potential for thiol delivery to the liver. Similar results were also observed for acetaminophen (APAP)-induced hepatopathy models. Flow cytometric data further confirmed that an increase in F4/80(+)/ROS(+) cells was dramatically decreased by SH-Man-HSA. The administration of SH-Man-HSA at 4 hours following a Con-A or APAP injection also exhibited a profound hepatoprotective action against these hepatitis models, whereas this was not observed for NAC. It can be concluded therefore that SH-Man-HSA has great potential for use in a rescue therapy for hepatopathy as a nanoantioxidant because of its ability to efficiently and rapidly deliver thiols to CD68(+)/CD206(+) KC.


Asunto(s)
Albúminas/uso terapéutico , Antígenos CD/metabolismo , Antígenos de Diferenciación Mielomonocítica/metabolismo , Antioxidantes/uso terapéutico , Enfermedad Hepática Inducida por Sustancias y Drogas/tratamiento farmacológico , Glicoproteínas/uso terapéutico , Macrófagos del Hígado/efectos de los fármacos , Lectinas Tipo C/metabolismo , Lectinas de Unión a Manosa/metabolismo , Nanopartículas/química , Receptores de Superficie Celular/metabolismo , Acetaminofén/farmacología , Enfermedad Aguda , Albúminas/administración & dosificación , Albúminas/farmacocinética , Animales , Antioxidantes/administración & dosificación , Antioxidantes/farmacocinética , Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Concanavalina A/farmacología , Modelos Animales de Enfermedad , Citometría de Flujo , Glicoproteínas/administración & dosificación , Glicoproteínas/farmacocinética , Macrófagos del Hígado/metabolismo , Macrófagos del Hígado/patología , Masculino , Receptor de Manosa , Ratones Endogámicos C57BL
12.
Ther Drug Monit ; 36(5): 553-5, 2014 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-24632808

RESUMEN

: In this report, the authors described the unusual case of a patient in whom the plasma phenytoin concentration was unexpectedly not detected on a particle-enhanced turbidimetric inhibition immunoassay (PETINIA) technique, a typical immunoassay for phenytoin. The plasma concentration was measured using PETINIA and high-performance liquid chromatography in a 69-year-old male patient treated with fosphenytoin intravenously at the standard dose for 7 days. Although the plasma concentration of phenytoin was below the limit of detection (<0.5 mcg/mL) on PETINIA after the administration of fosphenytoin, the trough plasma concentration was estimated to be between 5 and 10 mg/L on high-performance liquid chromatography. When the plasma concentrations of IgM and IgG were measured using an enzyme-linked immunosorbent assay, the plasma IgG level was within the reference range, whereas the plasma IgM level was 2-3 times higher than the upper limit of the reference range. We concluded that the PETINIA method yielded a possible false-negative result regarding the phenytoin level in this patient, perhaps because of some hindrance to the measurement process by IgM. This case suggests that false-negative results should be considered when therapeutic drug monitoring reveals abnormally low values using PETINIA and that it is necessary to evaluate the plasma IgM level.


Asunto(s)
Monitoreo de Drogas/métodos , Reacciones Falso Negativas , Inmunoensayo/métodos , Inmunoglobulina M/sangre , Nefelometría y Turbidimetría/métodos , Fenitoína/sangre , Anciano , Anticonvulsivantes/sangre , Humanos , Masculino
13.
J Control Release ; 145(1): 9-16, 2010 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-20304018

RESUMEN

Human serum albumin (HSA), a non-glycosylated protein, is widely employed as carrier for drug delivery systems. A series of recombinant, mannosylated-HSA mutants (Man-rHSAs: D63N, A320T and D494N) and their triple mutant (TM-rHSA: D63N/A320T/D494N) were prepared, that can be selectively delivered to the liver via mannose receptor (MR) on the liver non-parenchymal cells. A pharmacokinetic analysis of (111)In-Man-rHSAs in mice showed that they were rapidly cleared from the blood circulation, and were largely taken up by the liver rapidly in the order: TM-rHSA>D494N>>A320T=D63N, consistent with their degree of mannosylation. In vivo competition experiments with an excess amount of chemically modified Man-BSA or mannan suggested that the hepatic uptake of TM-rHSA was selectively mediated by MR on Kupffer cells. Lastly, a TM-rHSA-NO conjugate, S-nitrosylated TM-rHSA, effectively delivered NO to the liver and then exhibited a significant inhibitory effect against hepatic ischemia/reperfusion injury model rats, accompanied by the induction of heme oxygenase-1.


Asunto(s)
Portadores de Fármacos/química , Lectinas Tipo C/metabolismo , Hígado/efectos de los fármacos , Lectinas de Unión a Manosa/metabolismo , Manosa/genética , Receptores de Superficie Celular/metabolismo , Proteínas Recombinantes/genética , Albúmina Sérica/genética , Animales , Western Blotting , Dicroismo Circular , Modelos Animales de Enfermedad , Portadores de Fármacos/farmacocinética , Electroforesis en Gel de Poliacrilamida , Células Endoteliales/efectos de los fármacos , Células Endoteliales/metabolismo , Hemo-Oxigenasa 1/metabolismo , Humanos , Macrófagos del Hígado/efectos de los fármacos , Macrófagos del Hígado/metabolismo , Hígado/irrigación sanguínea , Hígado/metabolismo , Manosa/química , Manosa/farmacocinética , Receptor de Manosa , Ratones , Ratones Endogámicos , Óxido Nítrico/metabolismo , Ratas , Ratas Sprague-Dawley , Especies Reactivas de Oxígeno/metabolismo , Proteínas Recombinantes/química , Proteínas Recombinantes/farmacocinética , Daño por Reperfusión/tratamiento farmacológico , Daño por Reperfusión/metabolismo , Albúmina Sérica/química , Albúmina Sérica/farmacocinética , Distribución Tisular
14.
J Biochem ; 137(5): 607-16, 2005 May.
Artículo en Inglés | MEDLINE | ID: mdl-15944414

RESUMEN

Circulating proteins modified by advanced glycation end-products (AGE) are mainly taken up by liver endothelial cells (LECs) via scavenger receptor-mediated endocytosis. Endocytic uptake of chemically modified proteins by macrophages and macrophage-derived cells is mediated by class A scavenger receptor (SR-A) and CD36. In a previous study using SR-A knockout mice, we demonstrated that SR-A is not involved in endocytic uptake of AGE proteins by LECs [Matsumoto et al. (2000) Biochem. J. 352, 233-240]. The present study was conducted to determine the contribution of CD36 to this process. Glycolaldehyde-modified BSA (GA-BSA) and methylglyoxal-modified BSA (MG-BSA) were used as AGE proteins. 125I-GA-BSA and 125I-MG-BSA underwent endocytic degradation by these cells at 37 degrees C, and this process was inhibited by several ligands for the scavenger receptors. However, this endocytic uptake of 125I-GA-BSA by LECs was not inhibited by a neutralizing anti-CD36 antibody. Similarly, hepatic uptake of (111)In-GA-BSA after its intravenous injection was not significantly attenuated by co-administration of the anti-CD36 antibody. These results clarify that CD36 does not play a significant role in elimination of GA-BSA and MG-BSA from the circulation, suggesting that the receptor involved in endocytic uptake of circulating AGE proteins by LEC is not SR-A or CD36.


Asunto(s)
Acetaldehído/análogos & derivados , Antígenos CD36/fisiología , Endocitosis , Células Endoteliales/metabolismo , Productos Finales de Glicación Avanzada/metabolismo , Hígado/metabolismo , Piruvaldehído/química , Receptores Inmunológicos/fisiología , Albúmina Sérica Bovina/metabolismo , Acetaldehído/química , Animales , Anticuerpos Monoclonales , Antígenos CD36/inmunología , Masculino , Ratones , Ratones Noqueados , Ácido Oléico/metabolismo , Ratas , Receptores Depuradores , Receptores Depuradores de Clase A , Albúmina Sérica Bovina/química
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