Energy Dependent Transport of Xenobiotics and Its Relevance to Multidrug Resistance

Rajendra      Sharma; Yogesh   C.   Awasthi; Yusong      Yang; Abha      Sharma; Sharad   S.   Singhal; Sanjay      Awasthi

Abstract

Transport mechanisms for the exclusion of toxic xenobiotics and their metabolites from cellular environment are crucial for living organisms. Accumulation of these toxins may affect a number of regulatory and other functions, ultimately leading to cell death. This trafficking of toxins and their metabolites is an energy dependent, primary active process, involving the hydrolysis of nucleotide triphosphates (ATP or GTP), while transferring substrate molecules across the cell membrane, against a concentration gradient of the substrate. Therefore, specific membrane associated proteins, known as efflux pumps, are required to remove these undesirable molecules from the cellular environment. These transport proteins have diverse structural characteristics with molecular weights ranging from 28 kDa to 190 kDa and a broad substrate specificity ranging from anionic to weakly cationic compounds. While these transport mechanisms constitute an important part of the cellular defense machinery, they also pose a formidable threat to the efficacy of chemotherapy against pathogenic bacteria and cancer cells. In cancer cells, the over expression of these proteins may confer a multidrug resistance (MDR) phenotype. This problem of MDR in cancer cells has so far been attributed to the two major families of efflux pumps, P-glycoprotein (Pgp) and multidrug resistance associated proteins (MRP), which belong to the ATP-binding cassette (ABC) super family. However, the existence of these pumps has not been able to explain all types of acquired MDR. Therefore, the importance of transport mechanisms other than these ABC-transporters cannot be ruled out. One such transporter is DNP-SG ATPase, whose identity has recently been established with RLIP76, a Ral binding GTPase activating protein known to be involved in the Ras-Rho-Ral mediated signaling mechanism. In the present article, we review the comparative functional, structural, and molecular characteristics of some transporters and discuss their role in xenobiotic transport and multidrug resistance.

Keywords: Xenobiotics, cationic compounds, ABC-transporters, acquired MDR, ATP-binding cassette (ABC), multidrug resistance

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