丹参组分对不同基因型有机阴离子转运多肽1B1转运氟伐他汀的影响

Effects of Salvia miltiorrhiza Bunge components on fluvastatin uptake of different genotypes organic anion transporting polypeptide 1B1

目的研究丹参组分对不同基因型有机阴离子转运多肽1B1转运氟伐他汀的影响。方法通过构建OATP1B1*1a、*5、*15-HEK293T体外细胞摄取模型,LC-MS/MS法测定氟伐他汀浓度,比较不同剂量丹参组分组与空白组间氟伐他汀摄取率的差异。结果氟伐他汀在OATP1B1*1a、OATP1B1*5、OATP1B1*15-HEK293T细胞模型中的摄取动力学参数K;分别为(17.59±2.32),(12.52±1.42)和(18.49±2.06)μmol·L^(-1);熊果酸、隐丹参酮和二氢丹参酮Ⅰ可以增加各基因型OATP1B1-HEK293T细胞氟伐他汀的摄取(P<0.05),10μmol·L^(-1)熊果酸对OATP1B1*1a、OATP1B1*5、OATP1B1*15的活性诱导可达37.93%,63.16%,42.86%,10μmol·L^(-1)隐丹参酮对OATP1B1*1a、OATP1B1*5、OATP1B1*15的活性诱导可达62.96%,80.39%,28.57%,800 nmol·L^(-1)二氢丹参酮Ⅰ对OATP1B1*1a、OATP1B1*5、OATP1B1*15的活性诱导可达37.78%,53.33%,27.08%;仅高浓度丹参酮Ⅰ可抑制氟伐他汀的摄取(P<0.05),1 600 nmol·L^(-1)丹参酮Ⅰ对OATP1B1*1a、OATP1B1*5、OATP1B1*15的活性抑制率为20.75%,27.78%,21.43%。结论 OATP1B1*5(521T>C)对氟伐他汀的转运存在确切影响,熊果酸、隐丹参酮和二氢丹参酮Ⅰ可能是丹参中影响OATP1B1转运氟伐他汀的主要活性组分。

Objective To investigate the effects of Salvia miltiorrhiza Bunge components on the fluvastatin uptake of different genotypes OATP1B1.Methods In vitro uptake models of OATP1B1*1a、*5、*15-HEK293T cells were built and the concentrations of fluvastatin were determined by LC-MS/MS.The effects of Salvia miltiorrhiza Bunge components on the activity of OATP1B1 were evaluated by comparing the difference of fluvastatin uptake rates between experimental groups and control group,respectively.Results The uptake kinetic parameter K;of fluvastatin in OATP1B1*1a,OATP1B1*5 and OATP1B1*15-HEK293T cells were (17.59±2.32),(12.52±1.42) and (18.49±2.06)μmol·L^(-1),respectively.Ursolic acid,cryptotanshinone and dihydrotanshinoneⅠcould increase the uptake of fluvastatin in OATP1B1-HEK293T cells of all three genotypes (P<0.05).The inductivity rates of OATP1B1*1a,OATP1B1*5 and OATP1B1*15-HEK293T cells were 37.93%,63.16%,42.86%at 10μmol·L^(-1)ursolic acid,62.96%,80.39%,28.57%at 10μmol·L^(-1)cryptotanshinone and 37.78%,53.33%,27.08%at800 nmol·L^(-1)dihydrotanshinoneⅠ.Only high concentrations of tanshinoneⅠcould inhibite the uptake of fluvastatin (P<0.05),the inhibition rates of OATP1 B1*1 a,OATP1 B1*5 and OATP1 B1*15-HEK293 T cells were 20.75%,27.78%,21.43%at 1 600 nmol·L^(-1)tanshinoneⅠ.Conclusion The mutation site 521 T>C of OATP1 B1*5 had a definite effect on fluvastatin transport and the ursolic acid,cryptotanshinone and dihydrotanshinoneⅠmay be the main active components affecting the transport activity of OATP1 B1 in Salvia miltiorrhiza Bunge.