Overview of ABC transporters
Lipid membranes function in the cell survival and homeostasis by providing a barrier between the interior of the cell and its exterior environment. An essential function of every cell is the ability to import nutrients as well as exporting waste products and signaling molecules. ATP-binding cassette (ABC) transporters play significant physiological and toxicological roles during these export and import processes. The hydrolysis of ATP is utilized by the ABC transporters to drive transport of substrates against their concentration gradients. Commonly, in eukaryotic cells these transporters are exporters while in prokaryotic cells they are both importers and exporters. Up to now, 50 ABC transporters have been identified in humans. Mutations in these transporters can cause a variety of genetic diseases, including bleeding, and many liver and eye disorders, all of which are resulted from the failure to export a specific ligand across a lipid bilayer.
It has been found that ABCB, ABCC, and ABCG families are all involved in the drug transport. Because they are expressed in transporting epithelia, including the intestine, liver, and kidney, they play a crucial role in the absorption, distribution, and removal of drugs. Many of them are also related to mulitidrug resistance (MDR) of tumor cells causing treatment failure in cancer. It has been well established that active efflux by ABC transporters in the small intestine is a major contributor to poor absorption and low bioavailability. Three major ABC transporters, ABCB1/P-gp/, MRP1 and BCRP, have been showed to localize to the apical/luminal membrane of enterocytes, and thus, are regarded to form a barrier to intestinal absorption of substrate drugs. Generally, they are expressed at high level in the brush border membrane of the intestine that can effectively pump drugs back into the intestinal lumen to limit the extent of substrate drug absorption. It is known that absorbed drugs must be transported from the site of administration to the site of action. Therefore, the poor BBB (blood-brain-barrier) permeability of the lipophilic drugs is due to the efflux functions of ABC transporters. More recently, other ABC transporters, such as MRP2 and BCRP have also been implicated in protecting the brain tissue against xenobiotics.
ABC transporters have a major role in host detoxification and protection of the body against xenobiotics. The apical expression of ABC transporters in the intestine, like P-gp and BCRP, prevents the entrance in the systemic circulation, and the action of these transporters results in a decreased drug concentration in the liver. The liver is the major site of xenobiotic metabolism in the body, in which enzymes, like the cytochrome P-450 (CYP) family members catalyze the oxidative metabolism of many drugs, eventually affecting both drug efficacy and toxicity. The defense mechanism formed by ABC transporters under physiological circumstances is directed against accumulation of potentially harmful compounds.
Transporters not only maintain the connectivity of metabolisms across different cell types but also determine the uptake and secretion profile of individual cells. Knowledge of the cellular transport system is fundamental to understand human metabolism. Major cellular transport system is carried out by the largest transporter gene family called ATP-binding cassette (ABC) transporter family. These proteins translocate a wide variety of substrates including lipids, sugars, amino acids, metal ions, peptides, and proteins, and a large number of hydrophobic compounds and metabolites across extra- and intracellular membranes. They have been mainly documented to play a major role in lipid transport and lipid-related disorders. ABCA1 is the key protein in controlling the cellular apolipoprotein-mediated lipid removal pathway. Mutations in the ABCA1 gene will lead to Tangier disease, which is a genetic disorder characterized by an abnormal lipoprotein profile and the accumulation of cholesterol esters in various tissues. Cholesterol efflux from Tangier-fibroblasts to lipid-poor apolipoproteins is defective, suggesting that ABCA1 has a key role in the modulation of the reverse cholesterol transport. A number of other ABC transporters have also been shown to play a role in lipid and cholesterol transport. The expression level of ABCG1 in human macrophages is greatly increased by cholesterol loading and by lipoprotein, implicating that this protein is involved in the metabolism of these lipids. In addition, ABCG5 and ABCG8, both close relatives of ABCG1, play a role in lipid metabolism. They were documented to work as obligate heretodimers, and both their function and correct cellular localization depend on this dimerization process. Furthermore, ABCB4 (MDR3) is a specific phosphatidyl choline transporter residing in the bile canalicular membrane in the liver.
Relations with diseases
In a situation of organ damage or disease, changes in the expression levels of ABC transporters have been observed, which is likely to lead to the increased load of harmful products of oxidative stress formed during an insult or to lead to the loss of efflux pumps in damaged tissues. In severe human liver diseases (primary cirrhosis, cell necrosis or chronic hepatitis), MRP2 is down-regulated, but P-gp, BCRP, MRP1 and MRP3 (ABCC3) is up-regulated, which prevents the accumulation of toxic bile constituents and further liver damage. Mutations in the ABCA1 gene result in Tangier disease, a genetic disorder characterized by an abnormal lipoprotein profile and the accumulation of cholesterol esters in various tissues. Modulations of the expression and function of these lipid transporter proteins may soon become an important pharmacological target.