About 50 ABC Small Molecule Pumps Are Known in Mammals

Discovery of the first eukaryotic ABC protein to be recognized came from studies on tumor cells and cultured cells that exhibited resistance to several drugs with unrelated chemical structures. Such cells eventually were shown to express elevated levels of a multidrug-resistance (MDR) transport protein known as MDR1. This protein uses the energy derived from ATP hydrolysis to export a large variety of drugs from the cytosol to the extracellular medium. The Mdr1 gene is frequently amplified in multidrug-resistant cells, resulting in a large overproduction of the MDR1 protein.

Most drugs transported by MDR1 are small hydrophobic molecules that diffuse from the medium across the plasma membrane, unaided by transport proteins, into the cell cy-tosol, where they block various cellular functions. Two such drugs are colchicine and vinblastine, which block assembly of microtubules. ATP-powered export of such drugs by MDR1 reduces their concentration in the cytosol. As a result, a much higher extracellular drug concentration is required to kill cells that express MDR1 than those that do not. That MDR1 is an ATP-powered small-molecule pump has been demonstrated with liposomes containing the purified protein (see Figure 7-5). The ATPase activity of these liposomes is enhanced by different drugs in a dose-dependent manner corresponding to their ability to be transported by MDR1.

About 50 different mammalian ABC transport proteins are now recognized (see Table 18-2). These are expressed in

abundance in the liver, intestines, and kidney—sites where natural toxic and waste products are removed from the body. Substrates for these ABC proteins include sugars, amino acids, cholesterol, peptides, proteins, toxins, and xenobiotics. Thus the normal function of MDR1 most likely is to transport various natural and metabolic toxins into the bile, intestinal lumen, or forming urine. During the course of its evolution, MDR1 appears to have acquired the ability to transport drugs whose structures are similar to those of these endogenous toxins. Tumors derived from MDR-expressing cell types, such as hepatomas (liver cancers), frequently are resistant to virtually all chemothera-peutic agents and thus difficult to treat, presumably because the tumors exhibit increased expression of the MDR1 or the related MDR2.

H Several human genetic diseases are associated with defective ABC proteins. X-linked adrenoleukodys-trophy (ALD), for instance, is characterized by a defective ABC transport protein (ABCD1) that is localized to peroxisomal membranes. This protein normally regulates import of very long chain fatty acids into peroxisomes, where they undergo oxidation; in its absence these fatty acids accumulate in the cytosol and cause cellular damage. Tangiers disease is marked by a deficiency of the plasmamembrane ABC protein (ABCA1) that transports phospholipids and possibly cholesterol (Chapter 18).

A final example is cystic fibrosis (CF), which is caused by a mutation in the gene encoding the cystic fibrosis transmembrane regulator (CFTR). This Cl_ transport protein is expressed in the apical plasma membranes of epithelial cells in the lung, sweat glands, pancreas, and other tissues. For instance, CFTR protein is important for resorption of Cl_ into cells of sweat glands, and babies with cystic fibrosis, if licked, often taste "salty." An increase in cyclic AMP (cAMP), a small intracellular signaling molecule, causes phosphorylation of CFTR and stimulates Cl_ transport by such cells from normal individuals, but not from CF individuals who have a defective CFTR protein. (The role of cAMP in numerous signaling pathways is covered in Chapter 13.) The sequence and predicted structure of the CFTR protein, based on analysis of the cloned gene, are very similar to those of MDR1 protein except for the presence of an additional domain, the regulatory (R) domain, on the cytosolic face. Moreover, the Cl~-transport activity of CFTR protein is enhanced by the binding of ATP. Given its similarity to other ABC proteins, CFTR may also function as an ATP-powered pump of some still unidentified molecule. I

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