Multidrug resistance-like proteins

Hirohashi T, Suzuki H, Ito K, Ogawa K, Kume K, Shimizu T et al. Hepatic expression of multidrug resistance-associated protein-like proteins maintained in eisai hyperbilirubinemic rats. Mol Pharmacol 1998 53(6) 1068-1075. 

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]. 

Fig. 13.2 Schematic of the Neuroprotective Gamma Glutamyl Cycle One of the neuroprotective roles of cortical astrocytes is maintenance of neuron glutathione (GSH) homeostasis. Astrocytes contain a highly effective GSH synthesis capacity and readily export the intact tripeptide into the extracellular milieu. The extrusion process is likely mediated by a multidrug resistance associated protein (Mrp). Once GSH is in the external compartment, it is hydrolyzed gamma glutamyl transpeptidase (7GT) to the dipeptide CysGly and glutamate. The dipeptide hydrolysis product is cleaved further by aminopeptidase N (APN) on the surface of the neuron to Cys and Gly. Cysteine is then transported into the neuron where it is a key determinant of neuron GSH synthesis (See also Color Insert)...

Intestinal excretion is an important mechanism in the elimination of flavonoid conjugates [82-84]. This is likely mediated by the multidrug resistance-associated protein (MRP) pumps. MRPs actively export conjugated metabolites out of the small intestine back into the intestinal lumen and so prevent or reduce systemic circulation [85]. An experiment using cultured Caco-2 cells showed that two metabolites of epicatechin were excreted on the apical side of the cells. Their elimination has been attributed to MRP-2, as efflux was significantly reduced by a competitive MRP-2 inhibitor [86]. Conversely, intestinal perfusion experiments with catechin indicate that catechin metabolites are not substrates for these transport proteins [49]. 

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. 

Emanuel SL, Chamberlin HA, Cohen D (1999) Antimitotic drugs cause increased tumorigenidty of multidrug resistant cells. Int J Oncol 14 487-494 Emoto Y, Manome Y, Meinhardt G, Kisaki H, Kharbanda S, Robertson M, Ghayur T, Wong WW, Kamen R, Weichsdbaum R, Kufe D (1995) Proteolytic activation of protein kinase C delta by an ICE like protease in apoptotic cells. EMBO J 14 6148-6156... 

Cells have been stained successfully for nuclear proteins related to proliferation (for example, PCNA, Ki-67, and various cyclins, which will be discussed in the chapter on DNA) and to tumor suppression (for example, p53, c-myc, and the retinoblastoma gene product). They have also been stained for proteins bound to interior membrane surfaces (e.g., Bcl-2, multidrug resistance protein [MDR], and P-gly-coprotein), and many strictly cytosolic proteins have been analyzed (like tubulin, hemoglobin, surface proteins that exist intracellularly at various stages of differentiation, and many cytokines). 

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