Ashida H, Oonishi T, Uyesaka N
Division of Biomedical Information Sciences, National Defense Medical College Research Institute, Saitama 359-8513, Japan.
J Theor Biol. 1998 Nov 21;195(2):219-32. doi: 10.1006/jtbi.1998.0787.
To clarify the mechanistic role of PGP (P-glycoprotein) in multidrug transport, we constructed a kinetic model composed of four compartments: (1) the extracellular space; (2) the space in the membrane; (3) the intracellular space; and (4) the pore-like space in the PGP molecule. The kinetics of the concentration of ADM (adriamycin) in each compartment were formulated based on the assumptions that (a) the movement of ADM between two compartments by diffusion is dependent on a dynamic distribution coefficient introduced here, (b) the uptake of ADM into the pore-like structure by the pump mechanism activated by ATP is described by enzyme kinetics, (c) the movement of ADM out of the pore-like structure to the extracellular medium through a valve-like mechanism is also expressed by enzyme kinetics. The mathematical analysis of the exact solution can explain the distinct effects of verapamil and vanadate on the accumulation and release of ADM, where verapamil inhibits the efflux by the valve-like mechanism and vanadate blocks the influx by the pump mechanism. We also performed a numerical calculation with this model for a quantitative explanation and found the valid parameter values to fit the experimental data. These results support the modified hydrophobic vacuum cleaner model.
为阐明P-糖蛋白（PGP）在多药转运中的机制作用，我们构建了一个由四个隔室组成的动力学模型：（1）细胞外空间；（2）膜内空间；（3）细胞内空间；以及（4）PGP分子中的孔状空间。基于以下假设制定了每个隔室中阿霉素（ADM）浓度的动力学：（a）ADM在两个隔室之间通过扩散的移动取决于此处引入的动态分配系数，（b）通过ATP激活的泵机制将ADM摄取到孔状结构中由酶动力学描述，（c）ADM通过类似阀门的机制从孔状结构移动到细胞外介质也由酶动力学表示。精确解的数学分析可以解释维拉帕米和钒酸盐对ADM积累和释放的不同影响，其中维拉帕米通过类似阀门的机制抑制流出，而钒酸盐通过泵机制阻断流入。我们还用这个模型进行了数值计算以进行定量解释，并找到了符合实验数据的有效参数值。这些结果支持了改进的疏水真空吸尘器模型。
