ATP-binding cassette superfamily

Hinoshita, E., Uchiumi, T., Taguchi, K., Kinukawa, N., Tsuneyoshi, M., Maehara, Y., Sugimachi, K. and Kuwano, M. (2000) Increased expression of an ATP-binding cassette superfamily transporter, multidrug resistance protein 2, in human colorectal carcinomas. Clinical Cancer Research, 6, 2401-2407. 

Conjugation of lipophilic xenobiotics to polar cellular constituents renders the xenobiotic more water-soluble. While the lipophilic parent xenobiotics could readily diffuse into the cells, the increase in polarity associated with conjugation greatly reduces the ability of the compound to diffuse across the lipid bilayer of the cell membrane thus trapping the compound within the cell. The polar conjugates must therefore rely upon active transport processes to facilitate efflux from the cell. Hepatocytes, as well as other cells involved in chemical detoxification, are rich with members of the ATP-binding cassette superfamily of active transport proteins (ABC transporters). Cellular efflux of xenobiotics by these transporters is often referred to as Phase III elimination because Phase I or II detoxification processes often precede and are a requirement of Phase III elimination. A detailed description and discussion of elimination and transporters is presented in Chapter 15. 

Pgp is a 170-kDa membrane-fixed glycoprotein and comprises two almost identical halves within 12 alpha-helical transmembrane-spanning domains and two intracellular ATP-binding sites. It belongs to the ABC (ATP-binding cassette) superfamily, which consists of more than 30 families transporting a tremendous variety of substrates. 

Gram-positive lactic acid bacteria possess several MDRs that excrete out of the cell a wide variety of mainly cationic lipophilic cytotoxic compotmds as well as many clinically relevant antibiotics. These MDRs are either proton/drug antiporters belonging to the major facilitator superfamily of secondary transporters or ATP-dependent primary transporters belonging to the ATP-binding cassette superfamily of transport proteins. 

The ATP binding cassette superfamily described previously for cancer cells and the malaria parasite... 

P-glycoprotein (P-gp) is a member of the ATP-binding cassette superfamily of membrane transport proteins responsible for the efflux of many drugs. It represents a major component of the blood-brain barrier and the intestinal barrier, and contributes to renal and biliary elimination of drugs. At the blood-brain barrier, P-gp is localized in the apical membrane of brain capillary endothelial cells and transports substrates into the blood. Therefore, P-gp limits the penetration into and retention of numerous compounds, including the antidepressants, within the brain and, thus, modulate their effectiveness and CNS toxicity. 

Currently, five different molecular classes of mdr efflux pumps are known [5], While pumps of the the ATP-binding cassette (ABC) transporter superfamily are driven by ATP hydrolysis, the other four superfamilies called resistance-nodulation-division (RND), major facilitator superfamily (MFS), multidrug and toxic compound extrusion (MATE), and small multidrag resistance transporter (SMR) are driven by the proton-motive force across the cytoplasmic membrane. Usually a single pump protein is located within the cytoplasmic membrane. However, the RND-type pumps which are restricted to Gram-negative bacteria consist of two additional components, a periplasmic membrane fusion protein (MFP) which connects the efflux pump to an outer... 

The presence at the BBB of members of the multidrug resistance-associated protein (MRPs) family, whose members preferentially transport anionic compounds, is still controversial. The seven members of the MRP family belong, like P-gp, to the ATP-binding cassette (ABC) protein superfamily. Mrpl has been found at the BBB in isolated rat brain capillaries, primary cultures of brain capillary endothelial cells and in immortalized capillary endothelial cells, but not in human brain capillaries [59]. Another member, MRP2 has been found at the luminal membrane of the brain endothelial cells [60]. However, further studies are required to show that there are MRP transporters at the BBB (Figure 15.5). As for P-gp, a functional Mrpl was found in primary cultured rat astrocytes [56] and it has been shown to take part in the release of glutathione disulfide from brain astrocytes under oxidative stress [61]. 

ABC transporters are multidomain systems that translocate substrates across membranes. A common characteristic is the well-conserved ATP binding cassette (ABC) domain that couples ATP hydrolysis to transport. Members of this group of proteins constitute the largest superfamily of transport components, and they are found in all organisms from Archaea to humans. According to the work of Dassa, who developed a classification based on the ATPase components, the ABC systems can be divided into a number of subfamilies (for details see http //www.pasteur.fr/recherche/unites/pmtg/abc/) [136]. 

Dean, M., Rzhetsky, A. and Allikmets, R. (2001) The human ATP-binding cassette (ABC) transporter superfamily. Genome Research, 11, 1156-1166. 

G. A. Altenberg. Structure of multidrug-resistance proteins of the ATP-binding cassette (ABC) superfamily. CurrMed Chem Anticancer Agents 4 53-62 (2004). 

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