Membrane Transporters and Drug Response

Transporters are membrane proteins that are present in all organisms. These proteins control the influx of essential nutrients and ions and the efflux of cellular waste, environmental toxins, and other xenobiotics. Consistent with their critical roles in cellular homeostasis, approximately 2000 genes in the human genome ~7 of the total number of genes code for transporters or transporter-related proteins. The functions of membrane transporters may be facilitated (equilibrative, not requiring energy) or active (requiring energy). In considering the transport of drugs, pharmacologists generally focus on transporters from two major superfamilies, ABC ( A TP b inding c assette) and SLC ( s o l ute c arrier) transporters. Most ABC proteins are primary active transporters, which rely on ATP hydrolysis to actively pump their substrates across membranes. There are 49 known genes for ABC proteins that can be grouped into seven subclasses or families (ABCA to ABCG) (Borst and Elferink, 2002). Among the best recognized transporters in the ABC superfamily are Pglycoprotein (P-gp, encoded by ABCB1 , also termed MDR1 ) and the cystic fibrosis transmembrane regulator (CFTR, encoded by ABCC7 ). The SLC superfamily includes genes that encode facilitated transporters and ion-coupled secondary active transporters that reside in various cell membranes. Forty-three SLC families with approximately 300 transporters have been identified in the human genome (Hediger, 2004). Many serve as drug targets or in drug absorption and disposition. Widely recognized SLC transporters include the serotonin and dopamine transporters (SERT, encoded by SLC6A4 ; DAT, encoded by SLC6A3 ). Drug-transporting proteins operate in pharmacokinetic and pharmacodynamic pathways, including pathways involved in both therapeutic and adverse effects (Figure 2–1).