School of Veterinary Medicine and Science, Sutton Bonington Campus, Sutton Bonington, University of Nottingham, Leicestershire LE12 5RD, UK.
Cell Biochem Biophys. 2011 Sep;61(1):103-13. doi: 10.1007/s12013-011-9166-8.
Multi-drug resistance (MDR) can be explained by a drug handling-type activity. In this context it is also necessary to consider the multi-specificity between drugs and drug transporters in order to explain MDR. Accordingly, the efficiency of drug efflux in MDR has always been a conceptual problem in biochemistry. Indeed, how one protein can expel, from cells, hundreds of compounds with high specificity is still controversial today. To safeguard the notion of biochemical specificity, many studies have suggested alternative mechanisms to Pgp-mediated drug resistance, which do not involve the handling of drugs. However, none of these studies have definitively ruled out the possibility concept of drug handling. Thus, until now it was not possible to imagine MDR without drug-transporter affinity or specificity. However, drug-transporter affinity is not always needed to generate what appears to be a very efficient chemical reaction. Indeed, based on the fact that bi-dimensional diffusion properties (i.e. diffusion in the membrane) are paramount to explain drug pumping-mediated MDR, it is possible to suggest how specific mathematical properties of random motions can be used to construct a model of Pgp-MDR, providing that Pgp oscillates between open/drug-accepting and closed/drug-expelling conformations. This different viewpoint highlights the fact that the multi-specificity of drug transporters and the "vacuum cleaner" hypothesis may actually be two sides of the same coin, both explained by the diffusion properties of drugs in the membrane. After retrieving basic results, predictions will be highlighted. Finally, the coherence of this model in the context of cancer biology will be discussed further.
多药耐药性 (MDR) 可以用药物处理型活性来解释。在这种情况下，还需要考虑药物和药物转运体之间的多特异性，以解释 MDR。因此，MDR 中药物外排的效率一直是生物化学中的一个概念问题。事实上，一种蛋白质如何能够从细胞中排出具有高度特异性的数百种化合物，今天仍然存在争议。为了维护生化特异性的概念，许多研究提出了替代 Pgp 介导的耐药性的机制，这些机制不涉及药物的处理。然而，这些研究都没有明确排除药物处理的概念。因此，到目前为止，人们还不可能想象没有药物转运体亲和力或特异性的 MDR。然而，产生似乎非常有效的化学反应并不总是需要药物转运体的亲和力。事实上，基于二维扩散特性（即膜内扩散）对于解释药物泵介导的 MDR 至关重要的事实，可以提出如何利用随机运动的特定数学特性来构建 Pgp-MDR 的模型，前提是 Pgp 在开放/药物接受和关闭/药物排出构象之间振荡。这种不同的观点强调了这样一个事实，即药物转运体的多特异性和“吸尘器”假说实际上可能是同一枚硬币的两面，都可以用药物在膜中的扩散特性来解释。在检索到基本结果后，将突出显示预测。最后，将进一步讨论该模型在癌症生物学背景下的一致性。
