ABC Transporters in Cholestatic Hepatocytes
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ABC Transporters in Cholestatic Hepatocytes
A cell must selectively translocate molecules across its plasma membrane to maintain the chemical composition of its cytoplasm distinct from that of the surrounding milieu. The most intriguing and, arguably, the most important membrane proteins for this purpose are the ABC (ATP-Binding Cassette) transporters. These proteins, found in all species, use the energy of ATP hydrolysis to translocate specific substrates across cellular membranes. The chemical nature of the substrates handled by ABC transporters is extremely diverse--from inorganic ions to sugars and large polypeptides--yet ABC transporters are highly conserved (Ref.1).

Transporters have been classified as primary, secondary, or tertiary active transporters. Secondary or tertiary active transporters, such as OAT (Organic Anion Transporter), OATP (Organic Anion-Transporting Polypeptides), NTCP (Na+-bile acid cotransporting protein), OCT1 (Organic Cation Transporter), OCTN, and PEPT, are driven by an exchange or cotransport of intracellular and/or extracellular ions. NTCP mediates the hepatic uptake of bile acids. Since NTCP is exclusively expressed on the sinusoidal membrane of the liver, this transporter may be used as a target for drug delivery to that organ. In addition, many members of OATP family (OATP1 & OATP2) mediate transport of a wide spectrum of amphipathic organic anions. In humans, the recently characterized human OATP-F is involved in the uptake of thyroxin from the blood into the CNS (Central Nervous System). The best characterized ABC transporters in the liver are: MDR1 (Multidrug Resistance Protein, also known as ABCB1), MDR3, BSEP (Bile Salt Export Pump) and MRP2 (Multi Drug Resistance Related Protein-2). MRP2, located on the bile canalicular membrane, is involved in the biliary excretion of clinically important anionic drugs as well as the intracellularly formed glucuronide and glutathione-conjugates of many drugs. After these enzymatic reactions, the conjugated metabolites produced are pumped out from hepatocytes into the bile. This ATP-dependent efflux transporter plays a physiologically important role as the "Phase-III" xenobiotic detoxification system (Ref.3). However, in some cases there is a major accumulation of drugs in the bile duct via MRP2 expressed on the bile canalicular membrane, which results in toxic effects on bile epithelial cells or gastrointestinal cells. The liver-specific ABC transporter MDR3 specifically transports phosphatidylcholine across the canalicular membrane during bile formation. By contrast, the multi-drug resistance protein MDR1 expels a variety of short-chain lipids and amphiphilic drugs from the cell. MDR1 mediates outward transport of natural lipids such as PAF (Platelet-Activating Factor), phosphatidylserine, sphingomyelin and glucosylceramide. The glutathione-dependent multidrug transporter MRP1 (ABCC1) transports short-chain phosphatidylcholine, phosphatidylserine, sphingomyelin and GlcCer analogs and help to maintain the outward orientation of natural choline phospholipids in the plasma membrane (Ref.4). In humans, MRP6 functions as a modulator of ATP-sensitive potassium channel and insulin release. Mutations and deficiencies in this protein result in hyperinsulinemic hypoglycemia of infancy, an autosomal recessive disorder of unregulated and high insulin secretion. Mutations have also been associated with non-insulin-dependent Diabetes Mellitus Type-II, an autosomal dominant disease of defective insulin secretion. Other ABC transporters have also been implicated in the transport of sterols.

Mutations in the genes encoding many of the 48 or so ABC transporters of human cells are associated with diseases such as cystic fibrosis, adrenoleukodystrophy, Tangier disease, Stargardt macular degeneration, and obstetric cholestasis. Mutations in the BSEP accounts for the syndrome of PFIC2 (Progressive Familial Intrahepatic Cholestasis) (Ref.6). Patients with PFIC3 have mutations in MDR3 that encode for the phospholipid export pump at the canalicular membrane. Bile salts are also not substrates for MDR2/MDR3, yet when this phospholipids export pump is deficient; bile salts do not form micelles and can result in damage of cholangiocytes and PFIC3 (Ref.2 & 5). Mutation in MRP2 leads to Dubin-Johnson Syndrome (Ref.7). Overexpression of certain ABC transporters is the most frequent cause of resistance to cytotoxic agents including antibiotics, antifungal, herbicides, and anticancer drugs.