This protein can also confer resistance to 9- 2-phosphonylmethoxyethyl guanine PMEG , a compound with neoplastic activity 37, Mutations affecting the human MRP6 gene were described in patients with pseudoxanthoma elasticum PXE , a rare heritable disorder, resulting in the calcification of elastic fibers. Functional studies demonstrated that MRP6 can mediate the transport of glutathione conjugates, e.
LTC4 and N-ethylmaleimide S-glutathione However, the physiological function and the role of ABCC6 in the pathogenesis of this disease are still unknown. This is the most frequent autosomal recessive disease within Caucasian populations, with a prevalence of 1 in 2, births. The CF symptoms mostly relate to the disruption of exocrine functions : in the sweat glands high sweat electrolyte , pancreas, bronchial glands chronic bronchopulmonary infection , intestinal glands meconium ileus , etc.
This protein provides a high-affinity binding site for sulfonylurea, which is widely used to treat patients with non-insulin-dependent diabetes mellitus The ABCD subfamily This subfamily consists of four human proteins, all ABC half-transporters, that require a partner half-transporter to form functional homo- or heterodimeric transporters.
They are localized in the peroxisomal membrane, and mutations in these genes cause different peroxisomal disorders. Adrenoleukodystrophy ALD is a severe X-linked disorder, the most frequent peroxisomal disorder, with a prevalence of 1 in 20, males, caused by mutations in the ABCD1 gene This neurodegenerative disease is characterized by the accumulation of the unbranched saturated fatty acids with a chain length of 24 to 30 carbons, as well as of cholesterol esters in the brain and in adrenal cortex. The first described member of this subfamily was the human homolog of the Drosophila white gene, ABCG1 The expression of this gene is regulated by cholesterol and lipoproteins in macrophages, suggesting that this protein is involved to the lipid metabolism in humans ABCG5 and ABCG8 are also playing a role in the lipid metabolism , and mutations of either of these genes cause a rare heritable disorder, called sitosterolemia In these patients the increased absorption of plant and fish sterols and their decreased biliary excretion cause a high level of toxic sitosterols in the blood, resulting in premature atherosclerosis and cardiac infarct.
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ABCG2 , a half-transporter causing mitoxantrone resistance in carcinoma cells and multidrug resistance in breast cancer , was first found in multidrug-resistant tumor cells not expressing either MDR1 or MRP1 ABCG2 functions as a high capacity drug transporter with a wide substrate specificity , and confers resistance to mitoxantrone, topotecan , and probably even methotrexate.
Many of the ABC transporters function as active transporters, they mediate the transport of substrates against a concentration gradient. This transport activity requires the energy of ATP hydrolysis,controlled by drug interaction, and coupled to the actual substrate translocation. Most probably the substrate recognition and binding occurs in some parts of the transmembrane domains , According to several reports, the hydrophobic substrates of MDR1 are recognized within the membrane bilayer or in its vicinity Similarly, in the case of MRP1 it has also been suggested that the transmembrane domains are involved in the drug interactions But the specific sequences responsible for the substrate recognition have not been identified as yet.
Recent reports have revealed a few key amino acids playing a role in the recognition of certain substrates in MDR1 , but the corresponding amino acids have not been found in MRP1. In active transporters the specific substrate binding enhances the ATPase activity of the transporter, so the transported substrate can promote the liberation of the energy required for its translocation. Vanadate probably replaces phosphate during ATP hydrolysis, and stabilizes a specific, transition state conformation see ref.
This substrate-modulated, vanadate-sensitive ATPase activity, representing the full transport cycle, can be directly measured and thus used in various ABC transporter assay systems.
In ABC transporters the catalytic reaction involves the formation of a transition state complex that contains an occluded nucleotide. This complex, when containing ADP, can be stabilized by vanadate 64 , and this vanadate-dependent nucleotide trapping is significantly modulated by compounds interacting with the transporter 6, 60, Again, this reaction can be used to study drug-protein interactions, as the concentration dependent modulation of nucleotide trapping correlates with the interaction of a given compound with the ABC proteins.
Still, we know relatively little about the detailed catalytic mechanism of ABC transporters, although several models have already been suggested to describe this mechanism The tissue distribution of these three major multidrug resistance proteins is overlapping but different. ABCC1 expression is high in all tissues, it is elevated in lung and the testis, and reduced in the liver. MDR1 is more restricted to tissues involved in the absorption and secretion MDR1 is also highly expressed in tissues with pharmacological barrier function, such as the blood-brain barrier, and the choroid plexus Recent reports have demonstrated that ABCG2 is highly expressed in the placenta, liver, intestine and in various stem cells In tissues where different multidrug transporters are present, the subcellular localization of these proteins can be a discriminating feature.
All multidrug transporters are localized predominantly in the plasma membrane. In contrast, MRP1 in polarized cells is localized solely in the basolateral membrane. The expression of ABCG2 was reported to be mostly apical The substrate specificity of MDR-ABC proteins exhibits as wide a variety as their tissue distribution and they share the ability to transport a wide range of compounds out of cells. The substrate specificities of these three proteins are again overlapping , but each transporter can handle unique compounds as well.
ABCG2 has also a remarkable range of transported substrates mitoxantrone, anthracyclins, topotecan, flavopiridol, and methotrexate - see 11, 68, In some cases, when different transporters with overlapping substrate profiles are located in the same cells, their affinity, capacity, and the cellular drug-concentrations determine the actual fate of the substrates. In hepatocytes, where MRP2 and MRP3 are both expressed, different conjugates are transported according to the transporters affinity and capacity.
MRP2 transports glucuronate conjugates with a relatively low affinity, but with high capacity, in contrast to MRP3, which is a high affinity, but low capacity transporter for these conjugates. Moreover, MRP-mediated transport is greatly increased by the presence of intracellular bile salts.
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Thus, under normal conditions glucuronate conjugates are extruded into the bile by MRP2, located in the apical membrane. However, at increasing cellular concentrations of glucuronate conjugates MRP3 can also remove a certain amount of these compounds into the blood stream, and defend the cells from the toxic materials The P-glycoprotein Pgp, MDR1, ABCB1 mediated multidrug resistance was the first discovered and probably still is the most widely observed mechanism in clinical multidrug resistance 1, 3, 5, Gallen, Switzerland Search for more papers by this author.
Alexander J. Beate I. Escher Corresponding Author E-mail address: escher eawag. Read the full text. Tools Request permission Export citation Add to favorites Track citation. Share Give access Share full text access. Share full text access.
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Browse All Figures Return to Figure. Different approaches can be used to give a more tightly regulated expression:.
Besides tightening regulation see above , other approaches exist to prevent losing the expression vector from the cells. Toxicity upon induction. Some proteins are so toxic for the cells that they do not only inhibit growth but also kill them. Thus, almost immediately after induction cells die and expression levels will be very low. Several approaches are possible to decrease the effects of protein toxicity:.
The expression of hydrophobic heterologous proteins usually membrane proteins is often toxic to the bacterial host. The following approaches can be used to lower its toxicity:. Use special host strains.
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