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561.
The effect of cell shape, cell density, contact with extracellular matrix and cell polarity on the phenobarbital (PB)-induced gene expression of CYP2B1 and CYP2B2 (CYP2B1/2B2) in adult rat hepatocytes was investigated. High cell density enhanced the induction of CYP2B1/2B2 gene expression by PB. Hepatocytes cultured on EHS gel showed a spherical cell shape and highly enhanced the induction of CYP2B1/2B2 gene expression by PB. Although monolayer hepatocytes cultured on type I collagen (TIC) and type IV collagen exhibited poor induction of CYP2B1/2B2 gene expression by PB, monolayer cells on laminin showed substantial induction. The addition of soluble laminin to media did not show any effect on induction in monolayer hepatocytes cultured on TIC. Dishes coated with different concentrations of immovable laminin demonstrated complicated effects. Coating with higher concentrations of laminin resulted in greater induction of CYP2B1/2B2 gene expression by PB. On the other hand, when hepatocytes were cultured on dishes coated with lower concentrations of laminin, they became round and greater induction of CYP2B1/2B2 gene expression by PB was observed. Spherical hepatocytes cultured on low concentrations of TIC also showed highly enhanced induction of CYP2B1/2B2 gene expression by PB. EHS gel overlay to hepatocytes cultured on TIC and collagen sandwich configurations that are known to induce cell polarity enhanced the induction by PB. The induction of CYP2B1/2B2 gene expression needed cytoskeleton organization, such as actin filament, microtubule filament and intermediate filament. These results demonstrate that cell shape, cell density, contact with extracellular matrix and cell polarity all play critical roles in the induction of CYP2B1/2B2 gene expression by PB. 相似文献
562.
Rat CYP2B1 and CYP2B2 and mouse CYP2B10 are dramatically induced by phenobarbital (PB) in liver. PB responsiveness requires the constitutive androstane receptor (CAR). However, dexamethasone treatment can also induce CYP2B genes in both rat and mouse liver. Three regions have been shown to be involved in conferring dexamethasone responsiveness on CYP2B2 reporter constructs. They are the PB response unit, a functional glucocorticoid response element at −1.3 kb in the 5′ flank and a weak element in the basal promoter. We report here the identification, by deletion analysis of the CYP2B2 5′ flank, of new glucocorticoid response elements or accessory factor sites. Moreover, we show that CAR acts as an accessory factor in the dexamethasone response in vivo of CYP2B10 protein in mice, by increasing both the basal and induced levels. We propose a model to explain the dexamethasone responsiveness of the CYP2B2 gene in which induction is mediated by a complex glucocorticoid response unit. 相似文献
563.
Standard antiepileptic drugs fail to block epileptiform activity in rat organotypic hippocampal slice cultures 总被引:1,自引:0,他引:1
BACKGROUND AND PURPOSE: Earlier studies had demonstrated that tonic-clonic seizure-like events (SLEs) resembling electrographic correlates of limbic seizures in animals and humans can be induced in organotypic hippocampal slice cultures (OHSCs). We have explored OHSCs for their suitability to serve as in vitro models of limbic seizures for studying seizure mechanisms and screening new antiepileptic compounds. EXPERIMENTAL APPROACH: OHSCs were cultivated according to the interface method. Neuronal activity and extracellular potassium concentration were recorded under submerged conditions. SLEs were induced by lowering magnesium concentration or by applying the potassium channel blocker 4-aminopyridine. The effects of standard antiepileptic drugs (AEDs), carbamazepine, phenytoin, valproic acid, clonazepam, diazepam and phenobarbital sodium on SLEs were analysed. KEY RESULTS: In more than 93% of OHSCs, AEDs did not prevent the induction of SLEs or stop ongoing seizure activity even when toxic concentrations were applied. This pharmacoresistance was independent of the method of seizure provocation, postnatal age at explantation (P2-P10) and cultivation time in vitro (2 months). SLEs were reversibly blocked by glutamate antagonists or the GABA(A)-agonist muscimol. CONCLUSIONS AND IMPLICATIONS: We present a simple to establish in vitro model of tonic-clonic SLEs that is a priori pharmacoresistant and thus has an advantage over animal models of pharmacoresistant seizures in which responders and non-responders can be sorted out only after an experiment. OHSCs could be suitable for exploring mechanisms of pharmacoresistant seizures and be used for the identification of new anticonvulsive compounds eventually effective in drug refractory epilepsy. 相似文献
564.
高效液相色谱法测定苯巴比妥、苯妥英、卡马西平的血药浓度 总被引:21,自引:0,他引:21
目的 :建立 HPL C法测定抗癫药苯巴比妥 (PB)、苯妥英 (PT)、卡马西平 (CBZ)的血药浓度。方法 :反相柱 ODS- Hy-persil(4.6 m m× 10 0 mm ,5︼m ) ,流动相为甲醇∶水 (5 2∶ 48) ,流速 0 .8m l/ m in,紫外检测波长 2 5 4nm ,以上 3药互为内标。标本经 CH2 Cl2 提取 ,蒸干后用流动相重溶进样。结果 :PB、PT、CBZ的保留时间分别为 3.2 2、5 .5 7、6 .80 m in;最低检测浓度分别为 0 .2 5、0 .5、0 .0 5︼g/ m l;线性范围分别为 2 .5~ 40、2 .5~ 40、1.2 5~ 2 0︼g/ ml;相对回收率分别为 10 1.49%、10 4.19%、98.70 % ;日内 RSD分别为 1.81%、5 .94%、1.81% ;日间 RSD分别为 6 .0 6 %、3.35 %、3.96 %。结论 :本法具快速、灵敏、实用等优点。 相似文献
565.
J S Isenberg L M Kamendulis D C Ackley J H Smith G Pugh A W Lington R H McKee J E Klaunig 《Toxicological sciences》2001,64(2):192-199
The tumor promotion stage of chemical carcinogenesis has been shown to exhibit a persistence of cellular effects during treatment and the reversibility of these changes upon cessation of treatment. Inhibition of gap-junctional intercellular communication and increased replicative DNA synthesis appear to be important in this process. The present study assessed the persistence and reversibility of gap-junctional intercellular communication inhibition, peroxisomal proliferation, and replicative DNA synthesis in livers from male F344 rats and B6C3F1 mice. Dietary administration of 20,000 mg/kg DEHP to male rats for 2 weeks decreased intercellular communication (67% of control) and enhanced replicative DNA synthesis (4.8-fold over control). Elevation of the relative liver weight and the induction of peroxisomal beta oxidation were also observed following treatment with 20,000 mg/Kg DEHP for 2 weeks. Following DEHP administration at a dose of 6000 mg/kg for 18 months, inhibition of gap-junctional intercellular communication persisted, and the relative liver weight and induction of peroxisomal beta oxidation remained elevated in both rats and male B6C3F1 mice. Treatment of rats and mice with phenobarbital for 18 months (500-mg/kg diet) also produced an increase in relative liver weight and a decrease in cell-to-cell communication. In recovery studies in which DEHP was administered to male F344 rats for 2 weeks and then withdrawn, the relative liver weight, rate of peroxisomal beta oxidation, increase in replicative DNA synthesis, and inhibition of gap-junctional intercellular communication returned to control values within 2 to 4 weeks after DEHP treatment ceased. Recovery studies with phenobarbital produced similar results. The primary active metabolite of DEHP, mono-2-ethylhexyl phthalate (MEHP), was detected in the livers of animals treated with DEHP for greater than 2 weeks. However, it could not be detected after removal of DEHP from the diet for 2 weeks. This study demonstrated that inhibition of gap-junctional intercellular communication, along with indicators of peroxisomal proliferation, including increased relative liver weight and enhanced peroxisomal beta oxidation, persist while DEHP treatment continues but reverses when treatment is stopped. Studies with phenobarbital produced a similar pattern of response. 相似文献
566.
四氢孕酮与苯巴比妥对保护小鼠最大电休克惊厥的协同作用(英文) 总被引:1,自引:1,他引:0
目的:观察四氢孕酮与苯巴比妥的抗惊厥相互作用。方法:采用小鼠最大电休克惊厥(MES)试验,测定四氢孕酮和/或苯巴比妥的保护作用;并采用小鼠大脑皮质膜制备,用氚标氟硝安定检测四氢孕酮和/或苯巴比妥对GABA_A受体复合物的调节。结果:苯巴比妥(0.5-50mg·kg~(-1))对小鼠最大电休克惊厥具剂量依赖性的保护作用,其ED_(50)为2.61mg·kg~(-1),95%可信限为1.59-4.26mg·kg~(-1)。同样,四氢孕酮(0.01-1.0mg·kg~(-1))也有剂量依赖性的保护作用,其ED_(50)为0.11(0.06-0.18)mg·kg~(-1)。四氢孕酮和苯巴比妥联合用药(1:20)的ED_(50)为0.73(0.44-1.21)mg·kg~(-1),Q值小于1。测定四氢孕酮和/或苯巴比妥增加氚标氟硝安定的结合,其浓度效应曲线与功能性协同作用的理论曲线相符。结论:四氢孕酮和苯巴比妥对抗小鼠最大电休克惊厥有协同作用;两者对增加氚标氟硝安定与GABA_A受体复合物的结合也有功能性协同作用。 相似文献
567.
目的采用反相高效液相色谱法同时测定气喘片中氨茶碱、盐酸麻黄碱、苯巴比妥和盐酸苯海拉明的含量。方法用Lichrosorb C18为色谱柱填料,以0.2%的三乙胺溶液(用50%的磷酸调节pH值2.5)甲醇(50∶50)为流动相,检测波长254 nm。结果4种成分能很好分离;氨茶碱、盐酸麻黄碱、苯巴比妥和盐酸苯海拉明的线性范围分别为20~300 μg·mL-1(r=0.9991),5~75μg·mL-1(r=0.9999),10~150μg·mL-1(r=0.9999)和5~75μg·mL-1(r=0.9997);平均回收率分别为101.18%,97.09%,100.50%和100.78%,RSD<2%(n=5)。结论方法快速、方便,适用于该复方制剂中4种成分的同时测定。 相似文献
568.
Yun J. Choi Hee J. Lee Jong W. Kwon Won B. Kim Junnick Yang Myung G. Lee 《Biopharmaceutics & drug disposition》1998,19(2):79-89
The pharmacokinetics of M1–M4, the metabolites of a new anthracycline antineoplastic agent, DA-125, were compared after intravenous (IV) administration of DA-125, 15 mg kg−1, to rats pretreated with enzyme inducers, such as phenobarbital (PBT, n = 14) and 3-methylcholanthrene (MCT, n = 15), or enzyme inhibitors, such as SKF-525A (SKT, n = 11) and chloramphenicol (CMT, n = 15), and to their control rats (n = 15 for PBC, CMC or SKC, and n = 11 for MCC). After IV administration of DA-125, the plasma concentrations of both M1 and M2 declined slowly from 1 to 2 h onwards to 8 h in all groups of rats due to the continuous formation of M2 from M1. The AUC0–8 h of M1 (47.1 versus 7.85 μg min mL−1) and M2 (20.7 versus 44.3 μg min mL−1) decreased significantly in the PBT group compared to those in the PBC group. However, the corresponding value of only M1 (74.6 versus 89.9 μg min mL−1) decreased significantly in the MCT group. The above data indicate that metabolism of M1 is increased by pretreatment with both PB and 3-MC, and that of M2 with PB, but not with 3-MC. The AUC0–8 h of both M1 (126 versus 78.5 μg min mL−1) and M2 (69.2 versus 44.3 μg min mL−1) increased significantly in the SKT group compared to the SKC group. However, the corresponding values were not significantly different between CMC and CMT groups. The above data indicate that the metabolism of both M1 and M2 is inhibited by pretreatment with SKF-525A, but not with CM. © 1998 John Wiley & Sons, Ltd. 相似文献
569.
李传雷 《临床心身疾病杂志》2005,11(3):215-216
目的探讨纳络酮、苯巴比妥、复方丹参注射液联用早期干预新生儿缺氧缺血性脑病的临床效果。方法将68例重度窒息复苏后的新生儿随机分为观察组和对照组,每组各34例。对照组给予常规治疗,观察组在常规治疗的基础上加用纳络酮、苯巴比妥、复方丹参注射液,观察两组发生惊厥和重度缺氧缺血性脑病的情况及病死率。结果观察组惊厥、重度缺氧缺血性脑病及病死率明显低于对照组,差异有显著性(P<0.05);CT检查脑白质低密度分布范围观察组重度改变者明显低于对照组,差异有显著性(P<0.05)。结论对重度窒息新生儿复苏后早期联合应用纳络酮、苯巴比妥、复方丹参注射液能有效预防新生儿惊厥及重度缺氧缺血性脑病的发生,降低病死率,改善预后。 相似文献
570.
KEVIN P. CHARPENTIER LISA L. VON MOLTKE JOSEPH W. POKU JEROLD S. HARMATZ RICHARD I. SHADER DAVID J. GREENBLATT 《Biopharmaceutics & drug disposition》1997,18(2):139-149
The effects of age on hepatic microsomal enzyme induction were studied in male CD-1 mice. Six week old and 1 year old animals were treated with either phenobarbital (80 mg kg−1) or saline once daily for 3 d. Twenty-four hours after the last treatment, animals were sacrificed and livers were harvested. Hepatic microsomal fractions were isolated and incubated with alprazolam, a triazolobenzodiazepine metabolized by cytochrome P-450-3A isoforms in humans. Metabolites were identified and quantitated by HPLC. All microsomal preparations produced two principal metabolites (α-OH- and 4-OH-alprazolam) while microsomes from phenobarbital-treated animals also produced a third metabolite (α, 4-dihydroxyalprazolam). Vmax , Km , and intrinsic clearance (Vmax/Km ratio) for both α-OH- and 4-OH-alprazolam in the saline-treated control animals were not significantly different between age groups. Vmax and intrinsic clearance for both metabolites were more than three times greater in phenobarbital-treated animals than in the control mice (p <0·001). Age did not influence the extent of induction, and both pathways were induced to approximately an equal extent. Thus the present in vitro study of liver microsomal preparations from male CD-1 mice does not delineate a mechanism for impaired alprazolam clearance in aging organisms in vivo. There is no evidence that age alters susceptibility to induction by phenobarbital. © 1997 by John Wiley & Sons, Ltd. 相似文献