川芎嗪和人参皂苷Rg1对Caco-2细胞p-糖蛋白功能和表达的影响
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摘要
一、目的
研究川芎嗪、人参皂苷Rg1单用以及它们合用时对p-糖蛋白功能和表达的影响。
二、方法
1.细胞培养以及形态学验证
培养Caco-2细胞、脐静脉内皮细胞ECV以及建立Caco-2单层细胞模型,用于研究川芎嗪和人参皂苷Rg1对p-糖蛋白功能和表达的影响。Caco-2细胞和ECV细胞均采用DMEM高糖培养基进行常规培养;细胞荧光免疫法进行p-糖蛋白表达验证;用Transwell板接种Caco-2细胞建立单层模型,采用细胞电位仪、荧光黄及普奈洛尔转运实验进行模型验证。
2.细胞毒性试验
采用MTT法,确定川芎嗪和人参皂苷Rg1的体外最大非细胞毒剂量,保证试验过程中细胞的活性。
3.罗丹明-123外排试验
以ECV细胞作阴性对照细胞,环孢素A作为p-糖蛋白功能抑制的阳性对照,使用高效液相紫外法研究川芎嗪和人参皂苷Rg1对p-糖蛋白底物罗丹明-123在Caco-2细胞中外排功能的影响。
4.罗丹明-123转运试验
环孢素A作为p-糖蛋白功能抑制的阳性对照,建立Caco-2单层细胞膜型,进一步研究川芎嗪和人参皂苷Rg1对罗丹明-123跨细胞膜转运功能的影响。
5.p-糖蛋白表达的测定
使用流式细胞仪分析川芎嗪和人参皂苷Rg1对Caco-2细胞上p-糖蛋白表达量的影响。
三、结果
1.细胞培养以及形态学验证
Caco-2和ECV细胞形态正常;Caco-2单层细胞模型紧密且完整,细胞旁及跨细胞转运通路通透性良好;Caco-2细胞强表达p-糖蛋白,ECV细胞弱表达p-糖蛋白;Caco-2单层细胞模型成功建立,可用于川芎嗪和人参皂苷Rg1对p-糖蛋白转运功能;ECV细胞适合作为阴性对照细胞。
2.细胞毒性试验
川芎嗪和人参皂苷Rg1分别在60～240μg/mL和6～24μg/mL范围内为非细胞毒性剂量,与细胞培养72小时后细胞的存活率大于90%。
3.川芎嗪和人参皂苷Rg1对罗丹明-123外排的影响
中、高浓度(120、240μg/mL)的川芎嗪能够显著降低罗丹明-123从Caco-2细胞的外排(p＜0.05)。中浓度的人参皂苷Rg1对罗丹明-123的外排影响不大,没有显著性差异(p＞0.05)。高浓度(20μg/mL)人参皂苷Rg1对外排有影响(p＜0.05)。中浓度的川芎嗪和人参皂苷kg1(120、20μg/mL)合用时,对罗丹明-123的外排有显著的协同抑制作用排(p＜0.05)。
4.川芎嗪和人参皂苷Rg1对罗丹明-123跨细胞膜转运的影响
中、高浓度(120、240μg/mL)的川芎嗪在0.5、1.0和1.5h能够使罗丹明-123从Caco-2单层细胞的肠腔侧到肠内壁侧的累积转运量显著增加(p＜0.05)。中浓度(10μg/mL)的人参皂苷Rg1对罗丹明-123的转运无显著影响(p＞0.05),高浓度的人参皂苷Rg1(20μg/mL)使罗丹明-123累积转运量显著增加(p＜0.05)。中浓度的人参皂苷Rg1和川芎嗪(120、20μg/mL)合用则对罗丹明-123从肠腔侧到肠内壁侧的累积转运量具有协同增强作用(p＜0.05)。
5.川芎嗪和人参皂苷Rg1对Caco-2细胞膜上p-糖蛋白表达的影响
中、高浓度(120、240μg/mL)的川芎嗪使Caco-2细胞的p-糖蛋白表达水平显著下调(p＜0.05)。中、高浓度(10、20μg/mL)的人参皂苷Rg1对p-糖蛋白的表达影响不大(p＞0.05)。中浓度的人参皂苷Rg1与中浓度的川芎嗪(10、120μg/mL)合用后,对p-糖蛋白的下调无协同作用(p＞0.05)。
四、结论
1.川芎嗪是p-糖蛋白的底物,与p-糖蛋白上Rh-123受体竞争性结合,减少p-糖蛋白对细胞内Rh-123的外排,增强Rh-123跨小肠上皮细胞的转运。同时川芎嗪也是p-糖蛋白的抑制剂,通过直接抑制p-糖蛋白的活性而影响p-糖蛋白功能,长时间应用TNP可通过下调p-糖蛋白的表达水平影响降低肠道P-gp的活性。
2.人参皂苷Rg1是p-糖蛋白的抑制剂,高浓度的人参皂苷Rg1通过直接抑制p-糖蛋白的外排转运功能而影响肠道p-糖蛋白的功能,长期应用不影响p-糖蛋白的表达水平。
3.当川芎嗪和人参皂苷Rg1合用时,对肠道p-糖蛋白功能具有协同抑制作用,但是对p-糖蛋白的表达无协同作用。
4.川芎嗪和人参皂苷Rg1和p-糖蛋白的其他底物合用时,可能会产生药物相互作用。川芎嗪和人参皂苷Rg1可增加其他p-糖蛋白底物的细胞内浓度,从而增加疗效或毒性作用。
5.川芎嗪有可能作为多药耐药逆转剂,提供很有价值的肿瘤辅助治疗方法。
OBJECTIVES
To study the effects of tetramethylpyrazine and ginsenoside Rg1 on p-glycoprotein function and expression in Caco-2 cells.
METHODS
1.Cell culture and morphological validated of cells
Caco-2 cells and ECV cells were cultured with DMEM(Dulbecco's Modified Eagle's Medium)which contains 10%FBS(Fetal Bovine Serum) in a humidified atmosphere of 95%air and 5%CO_2 at 37℃.The expression of p-glycoprotein in the cells was identified by immunofluorescence assy.The Caco-2 cells were cultured in transwell plates to establish monolayer model.The EVOM epithelial voltohmmeters,fluorescein and propranolol were used to test the function of the monolayer model.
2.Cytotoxicity studies in vitro
MTT(diphenyltetrazolium bromide)assay was used to find non-cytotoxicity dosage of tetramethylpyrazine and ginsenoside Rg1 in Caco-2 and ECV cells,and only when the survival rates of cells above 90%,the doses were considered as the non-cytotoxic dosage.
3.Effects of tetramethylpyrazine and ginsinoside Rg1 on the efflux of rhodamine-123 in cells
ECV cells were used as negative control cells.Cyclosporin A was used as positive control drug to posses the inhibitory effect on the function of p-glycoprotein.HPLC-UV was used for analysis the concentrations of rhodamine-123,which is a substrate of p-glycoprotein.
4.Effects of tetramethylpyrazine and ginsenoside Rg1 on rhodamine-123 transport though Caco-2 cells monolayer
Cyclosporin A was used as positive control drug to posses the inhibitory effect on the function of p-glycoprotein.HPLC-UV was used for analysis the concentrations of rhodamine-123 in the study of transport.
5.Measurement of expression of p-glycoprotein in cells
Flow cytometry was used to measure the expression of p-glycoprotein in Caco-2 and ECV cells.
RESULTS
1.Cell culture and morphological validated of cells
The expression of p-glycoprotein is plentiful in Caco-2 cells but sparse in ECV cells.The Caco-2 cell monolayer model was tight and intact.Caco-2 cell monolayer model was established successfully.Caco-2 cell and monolayer model were suitable for studying tetramethylpyrazine, ginsenoside Rg1 on the function and expression of p-glycoprotein.
2.In vitro cytotoxicity studies
Tetramethylpyrazine at concentrations ranging from 60 to 240μg/mL, ginsenoside Rg1 at concentrations ranging from 6 to 24μg/mL,were found to be non-cytotoxic towards the Caco-2 cells and ECV cells.
3.Effects of tetramethylpyrazine and ginsinoside Rg1 on the efflux of rhodamine-123 in cells
Middle and high(120 and 240μg/mL)concentrations of tetramethylpyrazine could decrease the efflux of rhodamine-123 from Caco-2 cells.Ginsenoside Rg1 at high concentration(20μg/mL)was observed to decrease p-glycoprotein mediated efflux.To combine tetramethylpyrazine with ginsenoside Rg1 at middle concentrations showed a great synergistic inhibition effect on the efflux of rhodamine-123 from Caco-2 cells.
4.Effects of tetramethylpyrazine and ginsinoside Rg1 on rhodamine-123 transport through Caco-2 cells monolayer
Both middle and high concentrations(120 and 240μg/mL)of tetramethylpyrazine could increase the transport of rhodamine-123 from the apical to basolateral.Ginsenoside Rg1 at high concentration (20μg/mL)was observed to increase the transport rate of rhodamine-123. Combining tetramethylpyrazine with ginsenoside Rg1 in middle concentrations(120 and 10μg/mL),increased rhodamine-123 level of Caco-2 cells that may be by synergistic effect.
5.Measurement of expression of p-glycoprotein in cells
Longer term(72h)co-incubation of the Caco-2 cells with middle and high concentrations of tetramethylpyrazine(120 and 240μg/mL)had the down-regulation effect of cellular p-glycoprotein level,but ginsenoside Rg1 didn't have this effect.Tetramethylpyrazine and ginsenoside Rg1 in middle concentration(120 and 10μg/mL)didn't show a synergistic effect on the expression the cellular p-glycoprotein level when co-incubation with Caco-2 cells in 72h.
CONCLUSIONS
1.Tetramethylpyrazine may be a substrate and inhibitor of p-glycoprotein. It could significantly inhibit the function of p-glycoprotein,and seemed to act directly on the activity of p-glycoprotein or be a binding site competitor of rhodamine-123.Tetramethylpyrazine could significantly decrease the expression of p-glycoprotein after incubated with Caco-2 cells in 72h.
2.Ginsenoside Rg1 may be an inhibitor of p-glycoprotein.It could significantly inhibit the activity of p-glycoprotein at high concentration. Longer term(72 h)co-incubation of the Caco-2 cell monolayer with ginsenoside Rg1 had no effect on p-glycoprotein levels.Ginsenoside Rg1 inhibited the activity of p-glycoprotein without decreasing the expression of Caco-2 cell monolayer.
3.Combining tetramethylpyrazine with ginsenoside Rg1 showed a great synergistic effect on p-glycoprotein mediated efflux and transport of rhodamine-123 in the cells but no synergistic effect on p-glycoprotein's expression.
4.The oral bioavailability of p-glycoprotein substrate may be influenced by tetramethylpyrazine and ginsenoside Rg1 or tetramethylpyrazine combining with ginsenoside Rg1 in the p-glycoprotein status.
5.Tetramethylpyrazine may represent a naturally novel multidrug resistance reversal agent,which is singificant for the chemotherapy against human cancer.
研究川芎嗪、人参皂苷Rg1单用以及它们合用时对p-糖蛋白功能和表达的影响。
二、方法
1.细胞培养以及形态学验证
培养Caco-2细胞、脐静脉内皮细胞ECV以及建立Caco-2单层细胞模型,用于研究川芎嗪和人参皂苷Rg1对p-糖蛋白功能和表达的影响。Caco-2细胞和ECV细胞均采用DMEM高糖培养基进行常规培养;细胞荧光免疫法进行p-糖蛋白表达验证;用Transwell板接种Caco-2细胞建立单层模型,采用细胞电位仪、荧光黄及普奈洛尔转运实验进行模型验证。
2.细胞毒性试验
采用MTT法,确定川芎嗪和人参皂苷Rg1的体外最大非细胞毒剂量,保证试验过程中细胞的活性。
3.罗丹明-123外排试验
以ECV细胞作阴性对照细胞,环孢素A作为p-糖蛋白功能抑制的阳性对照,使用高效液相紫外法研究川芎嗪和人参皂苷Rg1对p-糖蛋白底物罗丹明-123在Caco-2细胞中外排功能的影响。
4.罗丹明-123转运试验
环孢素A作为p-糖蛋白功能抑制的阳性对照,建立Caco-2单层细胞膜型,进一步研究川芎嗪和人参皂苷Rg1对罗丹明-123跨细胞膜转运功能的影响。
5.p-糖蛋白表达的测定
使用流式细胞仪分析川芎嗪和人参皂苷Rg1对Caco-2细胞上p-糖蛋白表达量的影响。
三、结果
1.细胞培养以及形态学验证
Caco-2和ECV细胞形态正常;Caco-2单层细胞模型紧密且完整,细胞旁及跨细胞转运通路通透性良好;Caco-2细胞强表达p-糖蛋白,ECV细胞弱表达p-糖蛋白;Caco-2单层细胞模型成功建立,可用于川芎嗪和人参皂苷Rg1对p-糖蛋白转运功能;ECV细胞适合作为阴性对照细胞。
2.细胞毒性试验
川芎嗪和人参皂苷Rg1分别在60～240μg/mL和6～24μg/mL范围内为非细胞毒性剂量,与细胞培养72小时后细胞的存活率大于90%。
3.川芎嗪和人参皂苷Rg1对罗丹明-123外排的影响
中、高浓度(120、240μg/mL)的川芎嗪能够显著降低罗丹明-123从Caco-2细胞的外排(p＜0.05)。中浓度的人参皂苷Rg1对罗丹明-123的外排影响不大,没有显著性差异(p＞0.05)。高浓度(20μg/mL)人参皂苷Rg1对外排有影响(p＜0.05)。中浓度的川芎嗪和人参皂苷kg1(120、20μg/mL)合用时,对罗丹明-123的外排有显著的协同抑制作用排(p＜0.05)。
4.川芎嗪和人参皂苷Rg1对罗丹明-123跨细胞膜转运的影响
中、高浓度(120、240μg/mL)的川芎嗪在0.5、1.0和1.5h能够使罗丹明-123从Caco-2单层细胞的肠腔侧到肠内壁侧的累积转运量显著增加(p＜0.05)。中浓度(10μg/mL)的人参皂苷Rg1对罗丹明-123的转运无显著影响(p＞0.05),高浓度的人参皂苷Rg1(20μg/mL)使罗丹明-123累积转运量显著增加(p＜0.05)。中浓度的人参皂苷Rg1和川芎嗪(120、20μg/mL)合用则对罗丹明-123从肠腔侧到肠内壁侧的累积转运量具有协同增强作用(p＜0.05)。
5.川芎嗪和人参皂苷Rg1对Caco-2细胞膜上p-糖蛋白表达的影响
中、高浓度(120、240μg/mL)的川芎嗪使Caco-2细胞的p-糖蛋白表达水平显著下调(p＜0.05)。中、高浓度(10、20μg/mL)的人参皂苷Rg1对p-糖蛋白的表达影响不大(p＞0.05)。中浓度的人参皂苷Rg1与中浓度的川芎嗪(10、120μg/mL)合用后,对p-糖蛋白的下调无协同作用(p＞0.05)。
四、结论
1.川芎嗪是p-糖蛋白的底物,与p-糖蛋白上Rh-123受体竞争性结合,减少p-糖蛋白对细胞内Rh-123的外排,增强Rh-123跨小肠上皮细胞的转运。同时川芎嗪也是p-糖蛋白的抑制剂,通过直接抑制p-糖蛋白的活性而影响p-糖蛋白功能,长时间应用TNP可通过下调p-糖蛋白的表达水平影响降低肠道P-gp的活性。
2.人参皂苷Rg1是p-糖蛋白的抑制剂,高浓度的人参皂苷Rg1通过直接抑制p-糖蛋白的外排转运功能而影响肠道p-糖蛋白的功能,长期应用不影响p-糖蛋白的表达水平。
3.当川芎嗪和人参皂苷Rg1合用时,对肠道p-糖蛋白功能具有协同抑制作用,但是对p-糖蛋白的表达无协同作用。
4.川芎嗪和人参皂苷Rg1和p-糖蛋白的其他底物合用时,可能会产生药物相互作用。川芎嗪和人参皂苷Rg1可增加其他p-糖蛋白底物的细胞内浓度,从而增加疗效或毒性作用。
5.川芎嗪有可能作为多药耐药逆转剂,提供很有价值的肿瘤辅助治疗方法。
OBJECTIVES
To study the effects of tetramethylpyrazine and ginsenoside Rg1 on p-glycoprotein function and expression in Caco-2 cells.
METHODS
1.Cell culture and morphological validated of cells
Caco-2 cells and ECV cells were cultured with DMEM(Dulbecco's Modified Eagle's Medium)which contains 10%FBS(Fetal Bovine Serum) in a humidified atmosphere of 95%air and 5%CO_2 at 37℃.The expression of p-glycoprotein in the cells was identified by immunofluorescence assy.The Caco-2 cells were cultured in transwell plates to establish monolayer model.The EVOM epithelial voltohmmeters,fluorescein and propranolol were used to test the function of the monolayer model.
2.Cytotoxicity studies in vitro
MTT(diphenyltetrazolium bromide)assay was used to find non-cytotoxicity dosage of tetramethylpyrazine and ginsenoside Rg1 in Caco-2 and ECV cells,and only when the survival rates of cells above 90%,the doses were considered as the non-cytotoxic dosage.
3.Effects of tetramethylpyrazine and ginsinoside Rg1 on the efflux of rhodamine-123 in cells
ECV cells were used as negative control cells.Cyclosporin A was used as positive control drug to posses the inhibitory effect on the function of p-glycoprotein.HPLC-UV was used for analysis the concentrations of rhodamine-123,which is a substrate of p-glycoprotein.
4.Effects of tetramethylpyrazine and ginsenoside Rg1 on rhodamine-123 transport though Caco-2 cells monolayer
Cyclosporin A was used as positive control drug to posses the inhibitory effect on the function of p-glycoprotein.HPLC-UV was used for analysis the concentrations of rhodamine-123 in the study of transport.
5.Measurement of expression of p-glycoprotein in cells
Flow cytometry was used to measure the expression of p-glycoprotein in Caco-2 and ECV cells.
RESULTS
1.Cell culture and morphological validated of cells
The expression of p-glycoprotein is plentiful in Caco-2 cells but sparse in ECV cells.The Caco-2 cell monolayer model was tight and intact.Caco-2 cell monolayer model was established successfully.Caco-2 cell and monolayer model were suitable for studying tetramethylpyrazine, ginsenoside Rg1 on the function and expression of p-glycoprotein.
2.In vitro cytotoxicity studies
Tetramethylpyrazine at concentrations ranging from 60 to 240μg/mL, ginsenoside Rg1 at concentrations ranging from 6 to 24μg/mL,were found to be non-cytotoxic towards the Caco-2 cells and ECV cells.
3.Effects of tetramethylpyrazine and ginsinoside Rg1 on the efflux of rhodamine-123 in cells
Middle and high(120 and 240μg/mL)concentrations of tetramethylpyrazine could decrease the efflux of rhodamine-123 from Caco-2 cells.Ginsenoside Rg1 at high concentration(20μg/mL)was observed to decrease p-glycoprotein mediated efflux.To combine tetramethylpyrazine with ginsenoside Rg1 at middle concentrations showed a great synergistic inhibition effect on the efflux of rhodamine-123 from Caco-2 cells.
4.Effects of tetramethylpyrazine and ginsinoside Rg1 on rhodamine-123 transport through Caco-2 cells monolayer
Both middle and high concentrations(120 and 240μg/mL)of tetramethylpyrazine could increase the transport of rhodamine-123 from the apical to basolateral.Ginsenoside Rg1 at high concentration (20μg/mL)was observed to increase the transport rate of rhodamine-123. Combining tetramethylpyrazine with ginsenoside Rg1 in middle concentrations(120 and 10μg/mL),increased rhodamine-123 level of Caco-2 cells that may be by synergistic effect.
5.Measurement of expression of p-glycoprotein in cells
Longer term(72h)co-incubation of the Caco-2 cells with middle and high concentrations of tetramethylpyrazine(120 and 240μg/mL)had the down-regulation effect of cellular p-glycoprotein level,but ginsenoside Rg1 didn't have this effect.Tetramethylpyrazine and ginsenoside Rg1 in middle concentration(120 and 10μg/mL)didn't show a synergistic effect on the expression the cellular p-glycoprotein level when co-incubation with Caco-2 cells in 72h.
CONCLUSIONS
1.Tetramethylpyrazine may be a substrate and inhibitor of p-glycoprotein. It could significantly inhibit the function of p-glycoprotein,and seemed to act directly on the activity of p-glycoprotein or be a binding site competitor of rhodamine-123.Tetramethylpyrazine could significantly decrease the expression of p-glycoprotein after incubated with Caco-2 cells in 72h.
2.Ginsenoside Rg1 may be an inhibitor of p-glycoprotein.It could significantly inhibit the activity of p-glycoprotein at high concentration. Longer term(72 h)co-incubation of the Caco-2 cell monolayer with ginsenoside Rg1 had no effect on p-glycoprotein levels.Ginsenoside Rg1 inhibited the activity of p-glycoprotein without decreasing the expression of Caco-2 cell monolayer.
3.Combining tetramethylpyrazine with ginsenoside Rg1 showed a great synergistic effect on p-glycoprotein mediated efflux and transport of rhodamine-123 in the cells but no synergistic effect on p-glycoprotein's expression.
4.The oral bioavailability of p-glycoprotein substrate may be influenced by tetramethylpyrazine and ginsenoside Rg1 or tetramethylpyrazine combining with ginsenoside Rg1 in the p-glycoprotein status.
5.Tetramethylpyrazine may represent a naturally novel multidrug resistance reversal agent,which is singificant for the chemotherapy against human cancer.
引文
[1]Jin Sun,Zhong-Gui He,Gang Cheng,et al.Multidrug resistance P-glycoprotein:crucial significance in drug disposition and interaction.Med Sci Monit,2004;10(1):5-14.
[2]Kirby B,Kharasch ED,Thummel KT,et al.Simultaneous Measurement of In Vivo P-glycoprotein and Cytochrome P450 3A Activities.J Clin Pharmacol,2006;46(11):1313-1319.
[3]Yi Han,Theresa MCT,Lee-YL,et al.Effects of capsaicin on p-gp function and expression in caco-2 cells.Biochemical Pharmacol,2006;7:1727-1734.
[4]Ofer M,Wolffram S,Koggel A,et al.modulation of drug transport by selected flavonoids:involvement of P-gp and OCT.Eur J Pharm Sci,2005;25(2-3):263-271.
[5]Efferth T,Davey M,Olbrich A,et al.Activity of Drugs from Traditional Chinese Medicine toward Sensitive and MDR1 or MRP1-Overexpressing Multidrug-Resistant Human CCRF-CEM Leukemia Cells.Blood Cells,2002;28(2):160-168.
[6]Chen J.Absorption and metabolism of genistein and its five isoflavone analogs in the human intestinal Caco-2 model.Cancer Chemother Pharmacol,2005;55(2):159-169.
[7]Wagner D.Intestinal drug efflux:formulation and food effects.Adv Drug Deliv Rev,2001;50(1):13-31.
[8]Stenberg P,Bergstrom CA,Luthman K,et al.Theoretical predictions of drug absorption in drug discovery and development.Clin Pharmacoki net,2002;41(11):877-899.
[9]Braun A,Hammerle S,Suda K,et al.Cell cultures as tools in biopharmacy.Eur J Pharm Sci,2000;11(2):51-60.
[10]Balimane PV,Pate K,Marino A.et al.Utility of 96 well Caco-2 cell system for increased throughput of P-gp screening in drug discovery.Eur J Pharm Biopharm,2004;58(1):99-105.
[11]Shiyin Yee.In vitro permeability across Caco-2 cells(Colonic)can predict in vivo(small intestinal)absorption in man-fact or myth.Pharmaceutical Research,1997;14(6):763-766.
[12]Liu ZQ,Jiang ZH,Liu L,et al.Mechanisms responsible for poor oral bioavailability of paeoniflorin:Role of intestinal disposition and interactions with sinomenine.Pharm Res,2006;23(12):2768-2780.
[13]Young AM,Audus KL,Proudfoot J,et al.Tetrazole compounds:the effect of structure and pH on Caco-2 cell permeability.J Pharm Sci,2006;95(4):717-725.
[14]Zhou SF,Lim LY,Chowbay B.Herbal modulation of P-glycoprotein.Drug Metab Rev,2004;36(1):57-104.
[15]赵永辰,陈信义.川芎嗪临床应用研究.中国医药学报,2002;17(1):53-56.
[16]Liu Y,Li X,Yuan HF.Progress of research on effects of ginsenoside Rg1 in promoting capability of leaming and memory.Zhong guo Zhong Xi Yi Jie He Za Zhi.2006;26(10):956-960.
[17]Leung KW,Pon YL,Wong RN,Wong AS.Ginsenoside-Rg1 induces vascular endothelial growth factor expression through the glucocorticoid receptor-related phosphatidylinositol 3-kinase/Akt and beta-catenin/T-cell factor-dependent pathway in human endothelial cells.J Biol Chem,2006;281(47):36280-36288.
[18]陈声武,王岩,王毅等.人参皂苷Rg-1和Rh-1抗肿瘤作用的研究.吉林大学学报(医学版),2003;01:30-33.
[19]He L,Liu GQ.Effects of various principles from Chinese herbal medicine on rhodamine123 accumulation in brain capillary endothelial cells.Acta Pharm Sin,2002;11(23):591-596.
[20]Yang L,Yan GP,Lian GR.Study on Study on reversal of multi drug resistance in leukemia by tetramethylphylpyrazine combining with cyclosporinA.Chin J Cancer,2000;19:304-306.
[21]Li JH,Yang PM.Study on ligustrazine in reversing mul-tidrug resistance of K562/ADM cell.Modern J integrated traditional Chinese and western med,2001;10:1405-1407.
[22]Liu XL,Tang J,Song J,et al.The effect of tetramethylpyrazine on the pharmacokinetics of intragastrically administered cyclosporine A in rats.Yao Xue Xue Bao,2006;41:882-887.
[23]Pang PK,Shan JJ,Chiu KW.Tetramethylpyrazine,a calcium antagonist.Planta Med,1996;62:431-435.
[24]Zhaohui Zhang,Yaotao Wei,Jingwu Hou,et al.Tetramethylpyrazine scavenges superoxide anion and decreases nitric oxide production in human polymorphonuclear leukocytes.Life Sciences,2003;72:2465-2472.
[25]Han M,Han LM,Wang QS,et al.Mechanism of oral absorption of panaxnotoginseng saponins.Yao Xue Xue Bao,2006;41(6):498-505.
[26]Meng Z,Zhang H,Zhao Y,Lan J,Du L.Transport behavior and efflux of Rgl in rat pulmonary epithelial cells.Biomed Chromatogr,2007(Mar 14),Abst.
[27]张向荣,张逸凡,钟大放.体外Caco-2细胞模型在药物吸收中的应用进展.中国医院药学杂志,2004;24(12):773-775.
[28]Shirasaka Y,Kawasaki M,Sakane T,et al.Induction of human P-glycoprotein in Caco-2 cells:development of a highly sensitive assay system for P-glycoprotein-mediated drug transport.Drug Metab Pharmacokinet,2006;21(5):414-423.
[29]Fekete MR,McBride WH,Pajonk F.Anthracyclines,proteasome activity and multi-drug-resistance.BMC Cancer,2005;5:108-114.
[30]Youdim KA,Qaiser MZ,Begley DJ,et al.Flavonoid permeability across an in situ model of the blood-brain barrier.Free Radic Biol Med,2004;36(5):592-604.
[31]赵立子,钟国平,黄民.LC/MS/MS测定大鼠血浆中普萘洛尔及其代谢物4-羟普萘洛尔、N-去异丙基普萘洛尔的浓度.药物分析杂志,2005;25(10):1203-1206.
[32]沙先谊,方晓玲,吴云娟.9-硝基喜树碱在Caco-2细胞模型中的体外摄取、转运及外排动力学.药学学报,2004;39(10):839-843.
[33]刘志伟,陈秉衡.Caco-2细胞单层模型及其在毒理学中的应用.卫生研究,2004;33(6):756-759.
[34]王立岩,佟晓红,宫桂兰等.人脐静脉内皮细胞的体外培养、鉴定及形态观察.白求恩医科大学学报,2000;26(1):26-28.
[35]杨海涛,王广基.Caco-2单层细胞模型及其在药学中的应用.药学学报,2000;35(10):797-800.
[36]Yee S.In vitro permeability across Caco-2 cells(colonic)can predict in vivo (small intestinal)absorption in man-fact or myth.Pharm Res,1997;14(6):763-766.
[37]Mosmann T.Rapid colorimetric assay for cellular growth and survival:application to proliferation and cytotoxicity assays.J Immunol Methods,1983;65:55-63.
[38]Garrigues A,Nugier J,Orlowski S,et al.A high-throughput screening microplate test for the interaction of drugs with p-glycoprotein.Analytical Biochemistry,2002;305:106-114.
[39]Pavek P,Staud F,Fendrich Z,et al.Examination of the functional activity of P-glycoprotein in the rat placental barrier using rhodamine 123.J Pharmacol Exp Ther.2003;305(3):1239-1250.
[40]Petriz J,O'Connor JE,Carmona MIs,et al.rhodamine 123 an appropriate fluorescent probe to assess P-glycoprotein mediated multidrug resistance in vinblastine-resistant CHO cells.Anal Cell Pathol,1997;14(3):129-140.
[41]Ryoko Yumoto,Teruo Murakami,Yuko Nakamoto,et al.Transport of Rhodamine 123,a P-Glycoprotein Substrate,across Rat Intestine and Caco-2 Cell Monolayers in the Presence of Cytochrome P-450 3A-Related Compounds.J Pharmacol Exp Ther,1999;289(1):149-155.
[42]He L,Liu GQ.Effects of various principles from Chinese herbal medicine on rhodamine123 accumulation in brain capillary endothelial cells.Acta Pharm Sin,2002;(23):591-596.
[43]Turkina AG,Baryshnikov AY,Sedyakhina NP,et al.Studies of P-glycoprotein in chronic myelogenous leukaemia patients:expression,activity and correlations with CD34 antigen.British Journal of Hamatology,1996;92(1):88-96.
[44]吴玉林,马秉亮,祝浩杰.洛美利嗪对大鼠脑微血管内皮细胞上P-糖蛋白活力的影响与P-gp及mdr1基因mRNA表达无关.中国临床药理学与治疗学,2006;11(1):45-50.
[45]李娟,张耀庭,曾伟等.应用考马斯亮蓝法测定总蛋白含量.中国生物制品学杂志,2000;13(1):118-121.
[46]陈晓梅,刘雅文,程熠等.考马斯亮蓝法蛋白定量标准曲线稳定性观察中国公共卫生,2006;22(3):380-381.
[47]Takano M,Hasegawa R,Fukuda T,Yumoto R,Nagai J,Murakami T.Interaction with P-glycoprotein and transport of erythromycin,midazolam and ketoconazole in caco-2 cells.European Journal of Pharmacology,1998;358(11):289-294.
[48]Breier A,Barancik M,Sulova Z,et al.P-glycoprotein—implications of metabolism of neoplastic cells and cancer therapy.Curr Cancer Drug Targets,2005;5(6):457-468.
[49]Xu D,Lu Q,and Hu X.Down-regulation of P-glycoprotein expression in MDR breast cancer cell MCF-7/ADR by honokiol.Cancer Lett,2006;243(2):274-280.
[50]Chieli E,Santoni-Rugiu E,Cervelli F,et al.Differential modulation of P-glycoprotein expression by dexamethasone and 3-methycholanthrene in rat hepatocyte primary cultures.Carcinogenesis,1994;15(2):335-341.
[51]Del Moral RG,OValle F,Andujar M,et al.Relationship between P-glycoprotein expression and cyclosporin A in kidney.An immunohistological and cell culture study.Am J Pathol,1995;146:392-398.
[52]Jette L,Beaulieu E,Leclerc JM,et al.Cyclosporin A treatment induces overexpression of P-glycoprotein in the kidney and other tissues.Am J Physiol Renal Physiol,1996;270:750-756.
[53]Del Moral RG,Andujar M,Ramirez C,et al.Chronic cyclosporin A nephrotoxicity,P-glycoprotein overexpression,and relationships with intrarenal angiotensin Ⅱ deposits.Am J Pathol,1997;151:1608-1705.
[54]Loscher W,Potschka H.Blood brain barrier active efflux transporters:ATP binding cassette gene family.NeuroRx,2005;2:86-98.
[55]Singh D,Alexander J,Owen A,et al.Whole-blood cultures from renal-transplant patients stimulated ex vivo show that the effects of cyclosporine on lymphocyte proliferation are related to P-glycoprotein expression.Transplantation,2004;77:557-561.
[56]Bao W,Chen BA,Gao F,et al.Effect of cyclosporine A,raloxifene and their combination on the reversion of multidrug resistance of K562/A02 line.Zhong guo Shi Yan Xue Ye Xue Za Zhi,2006;14:895-899.
[1]Jin Sun,Zhong-Gui He,Gang Cheng,et al.Multidrug resistance P-glycoprotein:crucial significance in drug disposition and interaction.Med Sci Monit,2004;10(1):5-14
[2]Braun A,Hammerle S,Suda K,et al.Cell cultures as tools in biopharmacy. Eur JPharm Sci,2000;11(2):51-60
[3]Brown D,Goosen TC,Chetty M,et al.Effect of oral contraceptives on the transport of chlorpromazine across the caco-2 intestinal epithelial cell line.Eur J Pharm Biopharm,2003;56(2):159-165
[4]D Angelisa I,Frigge G,Raimondi F,et al.Absorption of Fumonisin B_1 and aminopentol on an in vitro model of intestinal epithelium;the role of P-glycoprotein.Toxicon,2005;45(3):285-291
[5]Balimane PV,Pate K,Marino A.et al.Utility of 96 well Caco-2 cell system for increased throughput of P-gp screening in drug discovery.Eur J Pharm Biopharm,2004;58(1):99-105
[6]Pfrunder A,Gutmann H,Beglinger C Gene expression of CYP3A4,ABC-transporters(MDR1 and MRP1-MRP5)and hPXR in three different human colon carcinoma cell lines.JPharm Pharmacol,2003;55(1):59-66
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[8]He L,Liu GQ.Effects of various principles from Chinese herbal medicine on rhodamine-123 accumulation in brain capillary endothelial cells.Acta Pharmacol Sin,2002;23(7):591-560.
[9]包金凤,刘国卿.血脑屏障上的P-糖蛋白.国外医学药学分册,2000;27(3):154-158
[10]Megard I,Garrigues A,Orlowski S.et al.A co-culture-based model of human blood-brain barrier:applicat ion to active transport of indinavir and in vivo-in vitro correlation.Brain Res,2002;927(2):153-167
[11]Hosoya K,Sumio O,Tetsuya T.Recent advances in the brain to blood efflux transport across the blood-brain barrier.Int J Phar,2002;248:152-164
[12]Bloulton DW,Devano CL,Liston HL,et al.In vitro p-glycoprotein affinity for atypical and conventional antipsychotics.Life sci,2002;71(2):163-169
[13]Jin H,Audus KL.Effect of Bisphenol A.Drug Effiux in BeWo,a Human Trophoblast-like Cell Line.Placenta,2005;26(A):96-103
[14]梁延春,王秀丽.O~6-苄基鸟嘌呤对耐药细胞系K562/DOX多药耐药逆转作用的研究.白血病·淋巴瘤,2001;10(3):140-141
[15]Efferth T,Davey M,Olbrich A.et al.Activity of Drugs from Traditional Chinese Medicine toward Sensitive and MDR1- or MRP1-Overexpressing Multidrug-Resistant Human CCRF-CEM Leukemia Cells.Blood Cells Mol Dis,2002;28(2):160-168
[16]黎丹戎,张玮,唐东平.黄芩素对卵巢癌耐药细胞株A2780/ADM逆转作用实验研究.肿瘤,2004;24(2):111-113
[17]Anuchapreeda S,Leechanachai P,Smith MM,et al.Modulation of P-glycoprotein expression and function by cureuminin multidrug resistant human Kb cells.Biochem Pharmacol,2002,64(4):573-582.
[18]Yee S.In vit ro-perrneability across Caco-2 cells(colonic)can predict in vivo(small intestinal)absorption in man-fact or myth.Pharm Res,1997;14(6):763-766
[2]Kirby B,Kharasch ED,Thummel KT,et al.Simultaneous Measurement of In Vivo P-glycoprotein and Cytochrome P450 3A Activities.J Clin Pharmacol,2006;46(11):1313-1319.
[3]Yi Han,Theresa MCT,Lee-YL,et al.Effects of capsaicin on p-gp function and expression in caco-2 cells.Biochemical Pharmacol,2006;7:1727-1734.
[4]Ofer M,Wolffram S,Koggel A,et al.modulation of drug transport by selected flavonoids:involvement of P-gp and OCT.Eur J Pharm Sci,2005;25(2-3):263-271.
[5]Efferth T,Davey M,Olbrich A,et al.Activity of Drugs from Traditional Chinese Medicine toward Sensitive and MDR1 or MRP1-Overexpressing Multidrug-Resistant Human CCRF-CEM Leukemia Cells.Blood Cells,2002;28(2):160-168.
[6]Chen J.Absorption and metabolism of genistein and its five isoflavone analogs in the human intestinal Caco-2 model.Cancer Chemother Pharmacol,2005;55(2):159-169.
[7]Wagner D.Intestinal drug efflux:formulation and food effects.Adv Drug Deliv Rev,2001;50(1):13-31.
[8]Stenberg P,Bergstrom CA,Luthman K,et al.Theoretical predictions of drug absorption in drug discovery and development.Clin Pharmacoki net,2002;41(11):877-899.
[9]Braun A,Hammerle S,Suda K,et al.Cell cultures as tools in biopharmacy.Eur J Pharm Sci,2000;11(2):51-60.
[10]Balimane PV,Pate K,Marino A.et al.Utility of 96 well Caco-2 cell system for increased throughput of P-gp screening in drug discovery.Eur J Pharm Biopharm,2004;58(1):99-105.
[11]Shiyin Yee.In vitro permeability across Caco-2 cells(Colonic)can predict in vivo(small intestinal)absorption in man-fact or myth.Pharmaceutical Research,1997;14(6):763-766.
[12]Liu ZQ,Jiang ZH,Liu L,et al.Mechanisms responsible for poor oral bioavailability of paeoniflorin:Role of intestinal disposition and interactions with sinomenine.Pharm Res,2006;23(12):2768-2780.
[13]Young AM,Audus KL,Proudfoot J,et al.Tetrazole compounds:the effect of structure and pH on Caco-2 cell permeability.J Pharm Sci,2006;95(4):717-725.
[14]Zhou SF,Lim LY,Chowbay B.Herbal modulation of P-glycoprotein.Drug Metab Rev,2004;36(1):57-104.
[15]赵永辰,陈信义.川芎嗪临床应用研究.中国医药学报,2002;17(1):53-56.
[16]Liu Y,Li X,Yuan HF.Progress of research on effects of ginsenoside Rg1 in promoting capability of leaming and memory.Zhong guo Zhong Xi Yi Jie He Za Zhi.2006;26(10):956-960.
[17]Leung KW,Pon YL,Wong RN,Wong AS.Ginsenoside-Rg1 induces vascular endothelial growth factor expression through the glucocorticoid receptor-related phosphatidylinositol 3-kinase/Akt and beta-catenin/T-cell factor-dependent pathway in human endothelial cells.J Biol Chem,2006;281(47):36280-36288.
[18]陈声武,王岩,王毅等.人参皂苷Rg-1和Rh-1抗肿瘤作用的研究.吉林大学学报(医学版),2003;01:30-33.
[19]He L,Liu GQ.Effects of various principles from Chinese herbal medicine on rhodamine123 accumulation in brain capillary endothelial cells.Acta Pharm Sin,2002;11(23):591-596.
[20]Yang L,Yan GP,Lian GR.Study on Study on reversal of multi drug resistance in leukemia by tetramethylphylpyrazine combining with cyclosporinA.Chin J Cancer,2000;19:304-306.
[21]Li JH,Yang PM.Study on ligustrazine in reversing mul-tidrug resistance of K562/ADM cell.Modern J integrated traditional Chinese and western med,2001;10:1405-1407.
[22]Liu XL,Tang J,Song J,et al.The effect of tetramethylpyrazine on the pharmacokinetics of intragastrically administered cyclosporine A in rats.Yao Xue Xue Bao,2006;41:882-887.
[23]Pang PK,Shan JJ,Chiu KW.Tetramethylpyrazine,a calcium antagonist.Planta Med,1996;62:431-435.
[24]Zhaohui Zhang,Yaotao Wei,Jingwu Hou,et al.Tetramethylpyrazine scavenges superoxide anion and decreases nitric oxide production in human polymorphonuclear leukocytes.Life Sciences,2003;72:2465-2472.
[25]Han M,Han LM,Wang QS,et al.Mechanism of oral absorption of panaxnotoginseng saponins.Yao Xue Xue Bao,2006;41(6):498-505.
[26]Meng Z,Zhang H,Zhao Y,Lan J,Du L.Transport behavior and efflux of Rgl in rat pulmonary epithelial cells.Biomed Chromatogr,2007(Mar 14),Abst.
[27]张向荣,张逸凡,钟大放.体外Caco-2细胞模型在药物吸收中的应用进展.中国医院药学杂志,2004;24(12):773-775.
[28]Shirasaka Y,Kawasaki M,Sakane T,et al.Induction of human P-glycoprotein in Caco-2 cells:development of a highly sensitive assay system for P-glycoprotein-mediated drug transport.Drug Metab Pharmacokinet,2006;21(5):414-423.
[29]Fekete MR,McBride WH,Pajonk F.Anthracyclines,proteasome activity and multi-drug-resistance.BMC Cancer,2005;5:108-114.
[30]Youdim KA,Qaiser MZ,Begley DJ,et al.Flavonoid permeability across an in situ model of the blood-brain barrier.Free Radic Biol Med,2004;36(5):592-604.
[31]赵立子,钟国平,黄民.LC/MS/MS测定大鼠血浆中普萘洛尔及其代谢物4-羟普萘洛尔、N-去异丙基普萘洛尔的浓度.药物分析杂志,2005;25(10):1203-1206.
[32]沙先谊,方晓玲,吴云娟.9-硝基喜树碱在Caco-2细胞模型中的体外摄取、转运及外排动力学.药学学报,2004;39(10):839-843.
[33]刘志伟,陈秉衡.Caco-2细胞单层模型及其在毒理学中的应用.卫生研究,2004;33(6):756-759.
[34]王立岩,佟晓红,宫桂兰等.人脐静脉内皮细胞的体外培养、鉴定及形态观察.白求恩医科大学学报,2000;26(1):26-28.
[35]杨海涛,王广基.Caco-2单层细胞模型及其在药学中的应用.药学学报,2000;35(10):797-800.
[36]Yee S.In vitro permeability across Caco-2 cells(colonic)can predict in vivo (small intestinal)absorption in man-fact or myth.Pharm Res,1997;14(6):763-766.
[37]Mosmann T.Rapid colorimetric assay for cellular growth and survival:application to proliferation and cytotoxicity assays.J Immunol Methods,1983;65:55-63.
[38]Garrigues A,Nugier J,Orlowski S,et al.A high-throughput screening microplate test for the interaction of drugs with p-glycoprotein.Analytical Biochemistry,2002;305:106-114.
[39]Pavek P,Staud F,Fendrich Z,et al.Examination of the functional activity of P-glycoprotein in the rat placental barrier using rhodamine 123.J Pharmacol Exp Ther.2003;305(3):1239-1250.
[40]Petriz J,O'Connor JE,Carmona MIs,et al.rhodamine 123 an appropriate fluorescent probe to assess P-glycoprotein mediated multidrug resistance in vinblastine-resistant CHO cells.Anal Cell Pathol,1997;14(3):129-140.
[41]Ryoko Yumoto,Teruo Murakami,Yuko Nakamoto,et al.Transport of Rhodamine 123,a P-Glycoprotein Substrate,across Rat Intestine and Caco-2 Cell Monolayers in the Presence of Cytochrome P-450 3A-Related Compounds.J Pharmacol Exp Ther,1999;289(1):149-155.
[42]He L,Liu GQ.Effects of various principles from Chinese herbal medicine on rhodamine123 accumulation in brain capillary endothelial cells.Acta Pharm Sin,2002;(23):591-596.
[43]Turkina AG,Baryshnikov AY,Sedyakhina NP,et al.Studies of P-glycoprotein in chronic myelogenous leukaemia patients:expression,activity and correlations with CD34 antigen.British Journal of Hamatology,1996;92(1):88-96.
[44]吴玉林,马秉亮,祝浩杰.洛美利嗪对大鼠脑微血管内皮细胞上P-糖蛋白活力的影响与P-gp及mdr1基因mRNA表达无关.中国临床药理学与治疗学,2006;11(1):45-50.
[45]李娟,张耀庭,曾伟等.应用考马斯亮蓝法测定总蛋白含量.中国生物制品学杂志,2000;13(1):118-121.
[46]陈晓梅,刘雅文,程熠等.考马斯亮蓝法蛋白定量标准曲线稳定性观察中国公共卫生,2006;22(3):380-381.
[47]Takano M,Hasegawa R,Fukuda T,Yumoto R,Nagai J,Murakami T.Interaction with P-glycoprotein and transport of erythromycin,midazolam and ketoconazole in caco-2 cells.European Journal of Pharmacology,1998;358(11):289-294.
[48]Breier A,Barancik M,Sulova Z,et al.P-glycoprotein—implications of metabolism of neoplastic cells and cancer therapy.Curr Cancer Drug Targets,2005;5(6):457-468.
[49]Xu D,Lu Q,and Hu X.Down-regulation of P-glycoprotein expression in MDR breast cancer cell MCF-7/ADR by honokiol.Cancer Lett,2006;243(2):274-280.
[50]Chieli E,Santoni-Rugiu E,Cervelli F,et al.Differential modulation of P-glycoprotein expression by dexamethasone and 3-methycholanthrene in rat hepatocyte primary cultures.Carcinogenesis,1994;15(2):335-341.
[51]Del Moral RG,OValle F,Andujar M,et al.Relationship between P-glycoprotein expression and cyclosporin A in kidney.An immunohistological and cell culture study.Am J Pathol,1995;146:392-398.
[52]Jette L,Beaulieu E,Leclerc JM,et al.Cyclosporin A treatment induces overexpression of P-glycoprotein in the kidney and other tissues.Am J Physiol Renal Physiol,1996;270:750-756.
[53]Del Moral RG,Andujar M,Ramirez C,et al.Chronic cyclosporin A nephrotoxicity,P-glycoprotein overexpression,and relationships with intrarenal angiotensin Ⅱ deposits.Am J Pathol,1997;151:1608-1705.
[54]Loscher W,Potschka H.Blood brain barrier active efflux transporters:ATP binding cassette gene family.NeuroRx,2005;2:86-98.
[55]Singh D,Alexander J,Owen A,et al.Whole-blood cultures from renal-transplant patients stimulated ex vivo show that the effects of cyclosporine on lymphocyte proliferation are related to P-glycoprotein expression.Transplantation,2004;77:557-561.
[56]Bao W,Chen BA,Gao F,et al.Effect of cyclosporine A,raloxifene and their combination on the reversion of multidrug resistance of K562/A02 line.Zhong guo Shi Yan Xue Ye Xue Za Zhi,2006;14:895-899.
[1]Jin Sun,Zhong-Gui He,Gang Cheng,et al.Multidrug resistance P-glycoprotein:crucial significance in drug disposition and interaction.Med Sci Monit,2004;10(1):5-14
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