Multidrug Resistance and ABC Transporters

Cellular resistance to antibiotic and anticancer drugs is considered to be a major factor for the treatment of infectious diseases or cancers [120, 121]. Sometimes, microorganisms and cancer cells exhibit cross-resistance to a wide variety of functionally and structurally unrelated drugs [121,122]. This phenomenon is termed multidrug resistance (MDR), a concept introduced into scientific literature in the 1970s [123]. One of the most important mechanisms of multidrug resistance is via active drug export from the cell mediated by membrane proteins [121, 124, 125]. 

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Katiyar, S. K., Edlind, T. D., Identification and expression of multidrug resistance-related ABC transporter genes in Candida krusei, Med. Mycol. 2001, 39, 109-116. 

Lewis, D.R., Miller, N.D., Sphtt, B.L., Wu, G. Spalding, E.P. (2007). Separating the roles of acropetal and basipetal auxin transport on gravitropism with mutations in two Arabidopsis multidrug resistance-hke ABC transporter Genes. Plant Cell, 19,1838-1850. 

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 breast cancer resistance protein (BCRP) belongs to the G-branch of the ABC-transporter family (ABCG2). In contrast to most other ABC-proteins, BCRP consists of only one transmembrane domain (TDM) with one nucleotide binding fold (NBF) at its C-terminus. Because of this structural characteristic BCRP as well as other ABC-transporters with only one TMD are termed half transporters. To achieve functional activity these transporters have to form hetero- or homodimers. BCRP is involved in the multidrug resistance of certain tumors and transports endogenous compounds like cholesterol and steroid hormones. 

Limtraknl, P. et al.. Modulation of the function of three ABC drug transporters, P-glycoprotein (ABCBl), mitoxantrone resistance protein (ABCG2) and multidrug resistance protein 1 (ABCCl) by tetrahydroenrenmin, a major metabolite of cur-enmin. Mol. Cell Biochem., 296, 85, 2007. 

McAleer MA, Breen MA, White NL, Matthews N. pABCll (also known as MOAT-C and MRP5), a member of the ABC family of proteins, has anion transporter activity but does not confer multidrug resistance when overexpressed in human embryonic kidney 293 cells. J Biol Chem 1999 274(33) 23541-23548. 

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]. 

Chang, G. and Roth, C.B. (2001) Structure of MsbA from E. coli a homolog of the multidrug resistance ATP binding cassette (ABC) transporters. Science, 293, 1793-1800. 

Teodori E, Dei S, Martelli C, Scapecchi S, Gualtieri F (2006) The functions and structure of ABC transporters Implications for the design of new inhibitors of P-gp and MRP1 to control multidrug resistance (MDR). Curr Drug Targets 7 893-909. 

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