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991.
Harvey Wong Lois D Lehman-McKeeman Mary F Grubb Scott J Grossman Vasanthi M Bhaskaran Eric G Solon Helen S L Shen Ronald J Gerson Bruce D Car Bitao Zhao Brian Gemzik 《Toxicological sciences》2005,84(2):232-242
4-(3-pentylamino)-2,7-dimethyl-8-(2-methyl-4-methoxyphenyl)-pyrazolo-[1,5-a]-pyrimidine (DMP 904) is a potent and selective antagonist of corticotropin releasing factor receptor-1 (CRF1 receptor) with an efficacious anxiolytic profile in preclinical animal models. In subchronic toxicity studies in Sprague-Dawley rats, DMP 904 produced thyroid follicular cell hypertrophy and hyperplasia, and a low incidence of follicular cell adenoma. The current investigations were designed to determine the mode of action by which DMP 904 disrupts thyroid homeostasis in male rats. Five-day treatment with DMP 904 (300 mg/kg/day) dramatically lowered serum thyroxine (T4) to levels below detectable limits (< 1 microg/dl) by 72 h, with concurrent decreases in triiodothyronine (T3, about a 70% decrease) and increases in thyroid stimulating hormone (TSH; about a three-fold increase). DMP 904 increased [125I]T4 total body clearance (Cl tb) (38.21 +/- 10.45 ml/h) compared to control (5.61 +/- 0.59 ml/h) and phenobarbital-treated rats (7.92 +/- 1.62 ml/h). This increase in Cl(tb) was associated with a significant increase in biliary clearance (Cl bile) of unconjugated [125I]T4 (nearly 80-times control rates) and increased liver:blood ratios of T4, suggestive of enhanced hepatic uptake of T4. A single dose of DMP 904 (200 mg/kg) increased mRNA levels of hepatic cytochrome P450s (CYP 3A1 and CYP 2B1) and UDP-glucuronosyltransferases (UGT 1A1 and UGT 1A2). DMP 904 also induced mRNAs of the canalicular transporter, multi-drug resistance protein-2 (Mrp2) and sinusoidal transporters, organic anion transporting proteins (Oatp1 and Oatp2) within 24 h. Western blot analysis confirmed DMP 904 related increases in Oatp2 protein expression. Collectively, these data suggest that DMP 904 is an agonist of the constitutive androstane receptor (CAR) and pregnane X receptor (PXR) and that the decreased serum levels of T4 and T3 resulted from increased hepatobiliary clearance. However, DMP 904 is distinguished from other compounds associated with similar effects on thyroid hormone homeostasis because its effects were primarily related to increased biliary excretion of unconjugated T4. 相似文献
992.
Irreversible CYP3A inhibition by drugs constitutes one of the major causes of inhibition-based drug interactions. We evaluated time-dependent inactivation of CYP3A in cryopreserved human hepatocytes for six structurally diverse compounds known to exhibit this property. Inactivation kinetic parameters were also determined using human liver microsomes. Except for diclofenac, which did not cause CYP3A inactivation either in microsomes or in hepatocytes at concentrations up to 100 microM, time-dependent inactivation was observed in hepatocytes for amprenavir, diltiazem, erythromycin, raloxifene, and troleandomycin. The observed inactivation potency in hepatocytes (observed IC50) was compared with the potency predicted using microsomal parameters (predicted IC50). Despite satisfactory prediction for troleandomycin (1.35 and 2.14 microM for the predicted and observed IC50, respectively), over-prediction of inactivation was observed for raloxifene, amprenavir, and erythromycin (observed IC50 values 6.2-, 55-, and 7.8-fold higher, respectively, than the predicted IC50). By contrast, the observed IC50 for diltiazem in hepatocytes was approximately 4-fold lower than the IC50 predicted from microsomal data (under-prediction). After correcting for factors including nonspecific binding and inactivator consumption, prediction was significantly improved for raloxifene (the observed IC50 then became 2-fold higher than the predicted IC50) and for amprenavir to a lesser extent. A specific P-glycoprotein inhibitor, 4-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)-N-[2-(3.4-dimethoxyphenyl)ethyl]-6,7-dimethoxyquinazolin-2-amine (CP-100356), modulated the observed CYP3A inactivation potency by erythromycin and troleandomycin. In summary, these studies reveal three important factors that must be considered when microsomal inactivation parameters are used to predict inhibition-based drug interactions in intact cell systems. 相似文献
993.
994.
The purpose of this study was to evaluate the effects of MRZ 2/579, an uncompetitive N-methyl-D-aspartate antagonist, on infarct size, extent of swelling and neurological deficit in a model of transient middle cerebral artery occlusion in rats. Physiologically controlled Sprague-Dawley rats received 2 h MCAo by retrograde insertion of an intraluminal suture coated with poly-L-lysine. The agent (MRZ 2/579) or vehicle (sodium chloride 0.9%) was administered i.v. immediately after suture removal following a 2-h period of MCAo. Two experimental groups were studied: group A was treated by vehicle (bolus infusion:1 ml/kg for 10 min followed by infusion of 6 ml/kg/h over 6 h). Group B was treated by MRZ 2/579 (bolus infusion:10 mg/kg for 10 min followed by infusion of 6 mg/kg/h over 6 h). The neurological status was evaluated during occlusion (at 60 min) and daily for 3 days after MCAo. Brains were then perfusion-fixed, and infarct volumes and brain swelling were determined. MRZ 2/579 significantly improved the neurological score compared to vehicle-treated rats at 48 h (6.2+/-0.6 and 8.7+/-0.5, respectively; P<0.004) and 72 h after MCAo (5.2+/-0.6 and 8.4+/-0.5, respectively; P<0.001). Treatment with MRZ 2/579 also significantly reduced total infarct volume (29.3+/-11.1 and 83.2+/-16.5 mm(3), respectively; P<0. 01), cortical infarct volume (24.8+/-11.2 and 70.0+/-18.0 mm(3), respectively; P<0.04) and subcortical infarction (21.2+/-4.1 and 49. 6+/-4.5 mm(3), respectively; P<0.0002). Brain swelling was also markedly reduced compared with vehicle-treated rats (4.7+/-1.3 and 10.8+/-2.1%, respectively; P<0.02). These results demonstrate that treatment with MRZ 2/579, when administered promptly after reperfusion, confers neuroprotective effects on infarct volume, brain swelling, and neurological score compared to the vehicle group. 相似文献
995.
2000年中国总膳食样品中六六六和滴滴涕污染的溯源性分析 总被引:5,自引:0,他引:5
通过对 2 0 0 0年总膳食样品中有机氯农药残留分析 ,发现南方二区和北方一区水产类样品六六六高残留。由两个地区分省的聚类样品溯源分析 ,结果发现湖北省鳊鱼六六六含量为 4 0 0 6 0 μg kg ,为南方二区水产类六六六含量的 88 8% ,黑龙江省鲤鱼六六六含量为 6 30 96 μg kg,为北方一区水产类六六六含量的90 3% ,这是造成两个地区水产类六六六高残留的主要原因。由六六六异构体构成比例及GC MS的确证分析提示 ,两个地区的水产类样品受到林丹的污染。本研究表明我国某些地区存在违规使用林丹的现象。为保证我国居民膳食安全性 ,加强六六六和滴滴涕残留监测仍是我国食品安全领域的长期任务 相似文献
996.
Zhao ZQ Nakamura M Wang NP Velez DA Hewan-Lowe KO Guyton RA Vinten-Johansen J 《The Journal of surgical research》2000,94(2):133-144
BACKGROUND: Myocardial injury during early reperfusion (R) has been well documented. However, the extent and time course of myocardial injury during late R are still unclear. The purpose of this study was to determine the extent of regional contractile and endothelial dysfunction and myocardial blood flow (MBF) defect as well as extension of infarction in association with neutrophil (PMN) actions during R. MATERIALS AND METHODS: A total of 29 dogs underwent a protocol of 1 h LAD ischemia followed by 6, 24, 48, and 72 h of R, respectively. Regional contractile function (sonomicrometry), MBF (colored microspheres), infarct size (triphenyltetrazolium chloride staining), and PMN localization (immunohistochemistry) were determined. RESULTS: Percentage segmental shortening at 6, 24, 48, and 72 h of R was significantly blunted (-1.8 +/- 1.2,* - 0.37 +/- 0. 6,* 0.04 +/- 0.2,* and 5.9 +/- 1.2* vs baseline 17.7 +/- 0.8). MBF (ml/min/g) was attenuated at 24 (0.27 +/- 0.03*), 48 (0.46 +/- 0. 07*), and 72 h of R (0.48 +/- 0.06*) vs 6 h of R (0.65 +/- 0.06). Infarct size increased from 6 (27 +/- 2%) to 24 h of R (41 +/- 2%*) with no further increase at 48 and 72 h of R, consistent with a peak of creatine kinase activity. PMN adherence (mm(2) endothelium) to left anterior descending coronary artery (LAD) segments was increased after 6 h of R (63 +/- 3*) vs nonischemic left circumflex coronary artery (LCX) segments (42 +/- 2) with a peak at 48 h of R (111 +/- 5*). Endothelium-dependent vascular relaxation in the LAD was also blunted at 6, 24, and 48 h of R. Immunostaining revealed CD18-positive PMNs were mainly accumulated in intravascular space during 6 h of R with an increase in migration of PMNs seen at 24 h of R, consistent with a peak of myeloperoxidase release. Myeloperoxidase activity in a given area at risk sample was significantly correlated with infarct extension during the first 24 h of R. CONCLUSIONS: These results provide pathologic evidence for myocardial injury during the extended R and a basis for exploration of interventions designed to limit myocardial injury after ischemia. (*P < 0.05 vs Baseline, 6 h of R and LCX segments.) Copyright 2000 Academic Press. 相似文献
997.
人体肝癌和正常肝脏细胞内硒与氧化应激机制的初步探讨 总被引:1,自引:0,他引:1
目的 探讨微量元素硒和氧化应激水平在肝癌发展中的作用。方法 采集了数例肝癌晚期切除样品及其癌旁正常组织 ,测定了正常肝脏组织和癌组织不同细胞器中硒的含量以及超氧化物歧化酶 (SOD)、谷胱甘肽过氧化物酶 (GSH -Px)、硫氧还蛋白还原酶 (TrxR)活性及谷胱甘肽 (GSH)和蛋白总巯基的含量。结果 Se在肝癌溶酶体 (P <0 0 5 )、微粒体 (P <0 0 5 )、细胞质中的含量高于正常肝组织 ,几种抗氧化酶酶的活性和巯基含量均高于正常肝。癌细胞中的Se含量要明显高于相应的癌旁周围正常肝细胞 ,尤其是细胞核、线粒体和细胞质。癌细胞线粒体、细胞质中几种抗氧化酶的活性以及巯基含量均高于相应的癌旁正常肝细胞。结论 癌细胞代谢旺盛 ,摄取更多的营养物质 ,从而造成周围正常细胞营养素的缺乏 ,抗氧化能力的下降 ,其机制还有待进一步研究 相似文献
998.
缺锌大鼠海马胆囊收缩素和一氧化氮合酶阳性细胞数目的变化 总被引:2,自引:0,他引:2
目的 观察缺锌对海马胆囊收缩素 (CCK)和一氧化氮合酶 (NOS)阳性细胞数的影响及其与动物行为变化的关系 ,研究缺锌对学习记忆影响的机制。方法 通过管饲低锌液体饲料复制缺锌大鼠模型。二周后 ,使用Y 迷宫实验检测动物学习记忆能力 ;采用ABC免疫组化法和NADPH d组化检测海马各区CCK和NOS阳性细胞数目。结果 与对照组相比 ,缺锌大鼠学习记忆能力明显下降 (P <0 0 5 ) ;缺锌大鼠血清锌水平明显降低 (P <0 0 5 ) ,但海马锌含量未见明显改变 ;缺锌大鼠海马CA1区和CA3区CCK和NOS阳性细胞数目均明显减少。结论 缺锌导致海马CA1和CA3区CCK和NOS阳性细胞数目减少可能是缺锌影响脑学习记忆功能的重要机制之一 相似文献
999.
抑制性消减杂交技术检测反式二羟环氧苯并芘转化细胞与正常细胞基因表达差异 总被引:1,自引:0,他引:1
目的 筛选 7,8 二羟 9,10 环氧苯并芘 (BPDE)转化细胞与正常细胞的基因表达差异。方法 以BPDE转化支气管上皮细胞 (16HBE)细胞为检测子 (tester) ,正常 16HBE细胞为驱动子 (driver) ,应用抑制性消减杂交方法构建cDNA消减文库 ,经 2次消减杂交和 2次PCR后 ,将巢式PCR产物插入TA载体克隆 ,随机挑选克隆进行鉴定和测序 ,并用斑点杂交法验证其同源性 ,将所得序列进行GenBank的BLAST分析。结果 发现了 7个在BPDE转化细胞中高表达的基因 ,为翻译延长因子 1α1、线粒体基因、溶解物载体家族 2 5、EphA2、酪氨酸 3 加单氧酶 色氨酸 - 5 -加单氧酶活化蛋白、乳酸脱氢酶A、TRIM2 8等 ,尚有一条在GenBank的已知基因中找不到对应序列 ,在EST序列中找到全长对应序列。结论 发现的高表达基因可能在BPDE的致癌机制中起作用 ,另外 ,可能有未知基因与BPDE的恶性转化作用有关。 相似文献
1000.