黄连素对P-糖蛋白底物在Caco-2和L-MDR1细胞跨膜转运的影响

目的研究黄连素(berberine,Ber)对P-糖蛋白底物环孢素(cyclosporine A,CsA)和地高辛在Caco-2和L-MDR1细胞跨膜转运的影响。方法以Caco-2、L-MDR1细胞为模型,在50μmol·L-1～5mmol·L-1Ber作用后,测定地高辛和CsA跨膜转运的转运率和表观渗透系数。结果Ber在50μmol·L-1～5mmol·L-1范围内可剂量依赖性地降低地高辛在Caco-2和L-MDR1细胞单层底端(B侧)至顶端(A侧)的转运。对于CsA在Caco-2细胞的转运,50μmol·L-1～5mmol·L-1的Ber不但剂量依赖性地降低CsA从B→A方向的转运,而且也明显增加其在A→B方向的转运。在Caco-2和L-MDR1细胞,Ber抑制地高辛B→A方向转运的IC50值分别为1.44mmol·L-1和1.24mmol·L-1。Ber抑制CsA在Caco-2细胞转运的IC50值为607μmol·L-1。结论Ber和CsA相互作用的机制可能涉及P-gp功能的抑制和饱和。

Effects of berberine on the transport of P-gp substrates across Caco-2 and L-MDR1 cell monolayers

Aim To investigate effects of berberine (Ber) on the transport of P-gp substrates including cyclosporine A (CsA) and digoxin across Caco-2 and L-MDR cell monolayers. Methods Permeability coefficients and transport rates of digoxin and CsA across Caco-2 and L-MDR1 monolayers were measured in the presence of Ber(50 μmol·L-1~5 mmol·L-1). Results The inhibition studies for digoxin transport showed a dose-dependent decrease in basal-to-apical direction across Caco-2 and L-MDR1 monolayers in the presence of Ber (50 μmol·L-1~5 mmol·L-1). Both a dose-dependent decrease in basal-to-apical direction and an increase in apical-to-basal direction were observed for CsA transport across Caco-2 monolayers with different concentrations of Ber. The IC50 values calculated for Ber-induced inhibition of digoxin transport are 1.44 mmol·L-1 in Caco-2 cells and 1.24 mmol·L-1 in L-MDR1 cells, respectively. The IC50 value for Ber-induced inhibition of CsA transport is 607 μmol·L-1 in Caco-2 cells. Conclusion It was suggested that the inhibition and saturation of P-gp transport activity might be involved in interactions between Ber and CsA.