Litman T, Zeuthen T, Skovsgaard T, Stein W D
Department of Oncology, Herlev Hospital, University of Copenhagen, Denmark.
Biochim Biophys Acta. 1997 Aug 22;1361(2):159-68. doi: 10.1016/s0925-4439(97)00026-4.
We have determined the kinetic parameters for stimulation and inhibition by 34 drugs of the P-glycoprotein ATPase in membranes derived from CR1R12 Chinese hamster ovary cells. The drugs chosen were sets of calmodulin antagonists, steroids, hydrophobic cations, hydrophobic peptides, chemotherapeutic substrates of P-glycoprotein, and some other drugs with lower affinity for P-glycoprotein. We studied how these kinetic parameters correlated with the partition coefficient and the Van der Waals surface area of the drugs. The maximum velocity of ATPase stimulation decreased with surface area and showed a suggestion of a maximum with increasing partition coefficient. The affinity of these drugs for P-glycoprotein showed no significant correlation with partition coefficient but was highly correlated with the surface area suggesting that binding between modulators and P-glycoprotein takes place across a wide interaction surface on the protein.
我们已经确定了34种药物对源自CR1R12中国仓鼠卵巢细胞的膜中P-糖蛋白ATP酶的刺激和抑制动力学参数。所选择的药物包括钙调蛋白拮抗剂、类固醇、疏水阳离子、疏水肽、P-糖蛋白的化疗底物以及其他一些对P-糖蛋白亲和力较低的药物。我们研究了这些动力学参数如何与药物的分配系数和范德华表面积相关。ATP酶刺激的最大速度随表面积降低，并显示出随分配系数增加而达到最大值的趋势。这些药物对P-糖蛋白的亲和力与分配系数无显著相关性，但与表面积高度相关，这表明调节剂与P-糖蛋白之间的结合发生在蛋白质上广泛的相互作用表面。
