目的用Cocktail探针药物法研究参麦注射液对大鼠细胞色素P450酶（CYP450）6种亚型活性的影响。方法将SD大鼠随机分组,实验组ip给予参麦注射液（10 m L/kg）,对照组ip给予等量生理盐水,诱导7 d,分别以非那西丁、安非他酮、甲苯磺丁脲、...目的用Cocktail探针药物法研究参麦注射液对大鼠细胞色素P450酶（CYP450）6种亚型活性的影响。方法将SD大鼠随机分组,实验组ip给予参麦注射液（10 m L/kg）,对照组ip给予等量生理盐水,诱导7 d,分别以非那西丁、安非他酮、甲苯磺丁脲、奥美拉唑、美托洛尔和咪达唑仑作为CYP1A2、CYP2B1、CYP2C9、CYP2C19、CYP2D6和CYP3A4的探针药物。UPLC-MS/MS法检测大鼠血浆中探针药物的血药浓度,采用DAS3.0软件估算药动学参数。结果与对照组相比,非那西丁、安非他酮和奥美拉唑的AUC0^∞、CL和Cmax显著降低（P〈0.05）,甲苯磺丁脲、美托洛尔和咪达唑仑的AUC0^∞、CL和Cmax无显著性差异。结论参麦注射液对大鼠CYP1A2、CYP2B1和CYP2C19亚型的活性有明显的抑制作用,而对CYP2C9、CYP2D6和CYP3A4亚型的活性无显著性影响。展开更多
AIM： To study the effect of celecoxib （CXB） on diethylnitrosamine activation through the regulation of cytochrome P450 in a hepatocarcinogenesis model.METHODS： Six-week-old male Sprague-Dawley rats were randomly d...AIM： To study the effect of celecoxib （CXB） on diethylnitrosamine activation through the regulation of cytochrome P450 in a hepatocarcinogenesis model.METHODS： Six-week-old male Sprague-Dawley rats were randomly divided into five groups, a non-treated group （NT）, a diethylnitrosamine-treated group （DEN）, a DEN＋CXB-treated group （DEN＋CXB）,and CXB 8 d-treated and CXB 32 d-treated groups. The effects of celecoxib on the enzymatic activities of CYP1A1, 2A, 2B1/2, and 2E1 were assessed in hepatic microsomes 24 h after DEN administration.Changes in CYPIA1 and CYP2B1/2 protein expression were also evaluated. The rate of DEN metabolism was measured by the production of the deethylation metabolite acetaldehyde, and the denitrosation metabolite nitrite.RESULTS： DEN＋CXB administration produced a significant increase in the enzymatic activities ofCYP2B1/2 and 1A1, whereas it did not change the activities of CYP2A and 2E1, compared to that of the DEN group. CXB treatment for eight days did not produce a significant effect on enzymatic activity when compared to the NT group; however, when it was administered for prolonged times （CXB 32 d group）,the enzymatic activities were increased in a similar pattern to those in the DEN＋CXB group. The observed increase in the enzymatic activities in the DEN＋CXB group was accompanied by an increase in the CYP2B1/2 protein levels; no changes were observed in the levels of CYPIA1. In vitro, CXB increased the denitrosation of DEN, a pathway of metabolic detoxification. The addition of SKF-525A, a preferential inhibitor of CYP2B, abrogated the denitrosation of DEN.CONCLUSION： These results suggest that the mechanism of action of CXB involves enhancement of the detoxification of DEN by an increasing denitrosation via CYP2B1/2.展开更多
背景:研究表明,脐带间充质干细胞可以诱导分化成肝样细胞,从而对肝损伤有一定的修复作用。目的:探讨牛磺酸与人脐带间充质干细胞移植联合治疗对肝损伤的修复作用。方法:48只健康SD大鼠给予56度白酒灌胃30 d建立慢性酒精性肝损伤模型,建...背景:研究表明,脐带间充质干细胞可以诱导分化成肝样细胞,从而对肝损伤有一定的修复作用。目的:探讨牛磺酸与人脐带间充质干细胞移植联合治疗对肝损伤的修复作用。方法:48只健康SD大鼠给予56度白酒灌胃30 d建立慢性酒精性肝损伤模型,建模后将其随机分为模型组,脐带间充质干细胞组及牛磺酸+脐带间充质干细胞组。模型组门静脉注射生理盐水1 m L,脐带间充质干细胞组门静脉移植1 mL脐带间充质干细胞悬液,牛磺酸+脐带间充质干细胞组门静脉注射牛磺酸0.28 g/L+1 m L脐带间充质干细胞悬液。移植后2周,检测各组大鼠血清超氧化物歧化酶、谷胱甘肽过氧化物酶、过氧化氢酶、丙氨酸氨基转移酶以及丙二醛、内毒素、白细胞介素4水平;采用RT-PCR方法检测肝细胞特征性功能蛋白CYP2B1的mRNA表达。结果与结论:(1)与模型组相比较,脐带间充质干细胞组、牛磺酸+脐带间充质干细胞组超氧化物歧化酶、谷胱甘肽过氧化物酶、过氧化氢酶、谷丙转氨酶水平均显著增高(P<0.05),丙二醛、内毒素、白细胞介素4水平均显著下降(P<0.05)。与脐带间充质干细胞组比较,牛磺酸+脐带间充质干细胞组超氧化物歧化酶、谷胱甘肽过氧化物酶、过氧化氢酶、谷丙转氨酶水平进一步增高(P<0.05),丙二醛、内毒素、白细胞介素4水平进一步下降(P<0.05);(2)与模型组、脐带间充质干细胞组比较,肝细胞特征性功能蛋白CYP2B1的mRNA表达在牛磺酸+脐带间充质干细胞组显著增高,差异有显著性意义(P<0.05);(3)以上实验结果表明,脐带间充质干细胞移植可以修复大鼠肝损伤,与牛磺酸联合使用后效果更佳,其可能与减少自由基对机体的损害有关。展开更多
Intraperitoneal carcinomatosis(PC)may occur with several tumor entities.The prognosis of patients suffering from PC is usually poor.Present treatment depends on the cancer entity and includes systemic chemotherapy,rad...Intraperitoneal carcinomatosis(PC)may occur with several tumor entities.The prognosis of patients suffering from PC is usually poor.Present treatment depends on the cancer entity and includes systemic chemotherapy,radiation therapy,hormonal therapy and surgical resection.Only few patients may also benefit from hyperthermic intraperitoneal chemotherapy with a complete tumor remission.These therapies are often accompanied by severe systemic side-effects.One approach to reduce side effects is to target chemotherapeutic agents to the tumor with carrier devices.Promising experimental results have been achieved using drug-eluting beads(DEBs).A series of in vitro and in vitro experiments has been conducted to determine the suitability of their extravascular use.These encapsulation devices were able to harbor CYP2B1producing cells and to shield them from the hosts immune system when injected intratumorally.In this way ifosfamide-which is transformed into its active metabolites by CYP2B1-could be successfully targeted into pancreatic tumor growths.Furthermore DEBs can be used to target chemotherapeutics into the abdominal cavity for treatment of PC.If CYP2B1 producing cells are proven to be save for usage in man and if local toxic effects of chemotherapeutics can be controlled,DEBs will become promising tools in compartmentbased anticancer treatment.展开更多
文摘目的用Cocktail探针药物法研究参麦注射液对大鼠细胞色素P450酶（CYP450）6种亚型活性的影响。方法将SD大鼠随机分组,实验组ip给予参麦注射液（10 m L/kg）,对照组ip给予等量生理盐水,诱导7 d,分别以非那西丁、安非他酮、甲苯磺丁脲、奥美拉唑、美托洛尔和咪达唑仑作为CYP1A2、CYP2B1、CYP2C9、CYP2C19、CYP2D6和CYP3A4的探针药物。UPLC-MS/MS法检测大鼠血浆中探针药物的血药浓度,采用DAS3.0软件估算药动学参数。结果与对照组相比,非那西丁、安非他酮和奥美拉唑的AUC0^∞、CL和Cmax显著降低（P〈0.05）,甲苯磺丁脲、美托洛尔和咪达唑仑的AUC0^∞、CL和Cmax无显著性差异。结论参麦注射液对大鼠CYP1A2、CYP2B1和CYP2C19亚型的活性有明显的抑制作用,而对CYP2C9、CYP2D6和CYP3A4亚型的活性无显著性影响。
基金Supported by Consejo Nacional de Ciencia y Tecnología (Mexico),grant 39525-M,and scholarship 119303 (M.E.S.N.)
文摘AIM： To study the effect of celecoxib （CXB） on diethylnitrosamine activation through the regulation of cytochrome P450 in a hepatocarcinogenesis model.METHODS： Six-week-old male Sprague-Dawley rats were randomly divided into five groups, a non-treated group （NT）, a diethylnitrosamine-treated group （DEN）, a DEN＋CXB-treated group （DEN＋CXB）,and CXB 8 d-treated and CXB 32 d-treated groups. The effects of celecoxib on the enzymatic activities of CYP1A1, 2A, 2B1/2, and 2E1 were assessed in hepatic microsomes 24 h after DEN administration.Changes in CYPIA1 and CYP2B1/2 protein expression were also evaluated. The rate of DEN metabolism was measured by the production of the deethylation metabolite acetaldehyde, and the denitrosation metabolite nitrite.RESULTS： DEN＋CXB administration produced a significant increase in the enzymatic activities ofCYP2B1/2 and 1A1, whereas it did not change the activities of CYP2A and 2E1, compared to that of the DEN group. CXB treatment for eight days did not produce a significant effect on enzymatic activity when compared to the NT group; however, when it was administered for prolonged times （CXB 32 d group）,the enzymatic activities were increased in a similar pattern to those in the DEN＋CXB group. The observed increase in the enzymatic activities in the DEN＋CXB group was accompanied by an increase in the CYP2B1/2 protein levels; no changes were observed in the levels of CYPIA1. In vitro, CXB increased the denitrosation of DEN, a pathway of metabolic detoxification. The addition of SKF-525A, a preferential inhibitor of CYP2B, abrogated the denitrosation of DEN.CONCLUSION： These results suggest that the mechanism of action of CXB involves enhancement of the detoxification of DEN by an increasing denitrosation via CYP2B1/2.
文摘背景:研究表明,脐带间充质干细胞可以诱导分化成肝样细胞,从而对肝损伤有一定的修复作用。目的:探讨牛磺酸与人脐带间充质干细胞移植联合治疗对肝损伤的修复作用。方法:48只健康SD大鼠给予56度白酒灌胃30 d建立慢性酒精性肝损伤模型,建模后将其随机分为模型组,脐带间充质干细胞组及牛磺酸+脐带间充质干细胞组。模型组门静脉注射生理盐水1 m L,脐带间充质干细胞组门静脉移植1 mL脐带间充质干细胞悬液,牛磺酸+脐带间充质干细胞组门静脉注射牛磺酸0.28 g/L+1 m L脐带间充质干细胞悬液。移植后2周,检测各组大鼠血清超氧化物歧化酶、谷胱甘肽过氧化物酶、过氧化氢酶、丙氨酸氨基转移酶以及丙二醛、内毒素、白细胞介素4水平;采用RT-PCR方法检测肝细胞特征性功能蛋白CYP2B1的mRNA表达。结果与结论:(1)与模型组相比较,脐带间充质干细胞组、牛磺酸+脐带间充质干细胞组超氧化物歧化酶、谷胱甘肽过氧化物酶、过氧化氢酶、谷丙转氨酶水平均显著增高(P<0.05),丙二醛、内毒素、白细胞介素4水平均显著下降(P<0.05)。与脐带间充质干细胞组比较,牛磺酸+脐带间充质干细胞组超氧化物歧化酶、谷胱甘肽过氧化物酶、过氧化氢酶、谷丙转氨酶水平进一步增高(P<0.05),丙二醛、内毒素、白细胞介素4水平进一步下降(P<0.05);(2)与模型组、脐带间充质干细胞组比较,肝细胞特征性功能蛋白CYP2B1的mRNA表达在牛磺酸+脐带间充质干细胞组显著增高,差异有显著性意义(P<0.05);(3)以上实验结果表明,脐带间充质干细胞移植可以修复大鼠肝损伤,与牛磺酸联合使用后效果更佳,其可能与减少自由基对机体的损害有关。
文摘Intraperitoneal carcinomatosis(PC)may occur with several tumor entities.The prognosis of patients suffering from PC is usually poor.Present treatment depends on the cancer entity and includes systemic chemotherapy,radiation therapy,hormonal therapy and surgical resection.Only few patients may also benefit from hyperthermic intraperitoneal chemotherapy with a complete tumor remission.These therapies are often accompanied by severe systemic side-effects.One approach to reduce side effects is to target chemotherapeutic agents to the tumor with carrier devices.Promising experimental results have been achieved using drug-eluting beads(DEBs).A series of in vitro and in vitro experiments has been conducted to determine the suitability of their extravascular use.These encapsulation devices were able to harbor CYP2B1producing cells and to shield them from the hosts immune system when injected intratumorally.In this way ifosfamide-which is transformed into its active metabolites by CYP2B1-could be successfully targeted into pancreatic tumor growths.Furthermore DEBs can be used to target chemotherapeutics into the abdominal cavity for treatment of PC.If CYP2B1 producing cells are proven to be save for usage in man and if local toxic effects of chemotherapeutics can be controlled,DEBs will become promising tools in compartmentbased anticancer treatment.
