Bcrp Mxr Abcp

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Neutral and basic amphiphatic xenobiotics

Primary, ATP

Bile salts, paclitaxel, vinblastine Primary, ATP

Organic anions Primary, ATP, GSH

GSH and GSH-, Gluc-, Sulf-conjugates

Leukotriene C4 (LTC4)

Anticancer drugs and neutral xenobiotics

Organic anions, GSH and other Primary, ATP, GSH conjugates similar to MRP1

GSH and other conjugates similar to MRP1 bile acids cAMP, cGMP, nucleotide analogues and organic anions cAMP, cGMP, nucleotide analogues and organic anions Cyclic nucleotides, nucleoside analogues, and anionic conjugates Mitoxantrone, prazosin, topotecan, irinotecan, gleevec, flavopiridol

Primary, ATP, GSH

Primary, ATP

Primary, ATP

Primary, ATP

Primary, ATP

Intestine, liver, kidney, BBB, placenta, plasma membrane (apical in epithelial cells) Liver (bile canicular membrane)

All tissues (basolateral in epithelial cells)

Liver, intestine, kidney, BBB, placenta (apical in epithelial cells)

Liver, intestine, kidney, pancreas (basolateral in epithelial cells) Lung, kidney, liver, intestine, prostate, testis, ovary, BBB (apical in epithelial cells) All tissues (basolateral in epithelial cells) Liver, kidney

Liver, intestine, placenta, BBB, stem cells, mammary gland (apical in epithelial cells)

Efflux

Efflux Efflux

Efflux

Efflux

Efflux

Efflux Efflux

Efflux

Ol CD

different ethnic origin. The effect of MDR1 polymorphisms on the pharmacokinetics of drugs such as digoxin, fexofenadine, cyclosporin A, and tacrolimus remains very controversial, but it seems to involve mainly their absorption by the gut.23 The C3435T SNP is most frequently associated with nortriptyline-induced postural hypotension in patients with major depression who are being treated with nortriptyline and fluoxetine.24 However, other studies have shown no association between antidepressant-induced respiratory depression and the MDR1 C3435T variation.25 These studies are considerably hampered by the lack of MDR1 haplotype analysis. A recent study by Yi etal.26 examined exons 12, 21, and 26 of the three most frequent SNPs and showed that the distribution of fexofenadine varied considerably among healthy Korean male volunteers. These subjects were allocated to one of six groups, depending on their drug pharmacokinetics. MDR1 polymorphism may also influence the susceptibility of an individual to diseases. The exon 26 allele is significantly more frequent in subjects with drug-resistant epilepsy, and the same exon seems to protect patients with parkinsonism, especially those with a history of exposure to pesticides (which are frequently substrates of P-gp).27'28 Additional studies that focus on haplotypes, environmental factors, and patient size and selection are needed to demonstrate just how MDR1 polymorphisms influence drug pharmacokinetics.

MDR1 activity can also be altered by a modulation of gene transcription. Transcription of the MDR1 gene can be modulated by exposure to xenobiotics or mediators of inflammation, as well as by cell stress. The pregnane X receptor (PXR) controls the transcription of MDR1 and is activated by several steroids, dietary compounds, toxicants, and a number of currently used drugs. PXR regulates several genes encoding phase I and II metabolism enzymes and transporters, like the ABC proteins MRP2 and MRP3 in the liver and intestine.29 This raises the question of whether there is a coordinated defense system. The body seems to have at least three lines of defense that can be activated in response to xenobiotics. P-gp could be the first reducing the uptake of substrates; phase I and II enzymes producing metabolites could be the second; while the third line of defense could be other transporters, like the MRPs, that excrete the metabolites.

ABCB11 is a second member of this family that can affect drug disposition. This transporter was first reported as the sister of P-gp and called SPGP, or BSEP (bile salt export pump). It is found mainly in the bile canicular membranes and participates in the secretion of bile salts, such as taurocholate, but it can confer resistance to paclitaxel and vinblastine.30 BSEP appears to be a key target of drug-induced cholestasis, which results in the intracellular accumulation of bile salts, whose detergent actions promote hepatocellular damage by interfering with mitochondrial functions. Cyclosporin A, rifampin, glibenclamide, and bosentan have been shown to inhibit rat BSEP-mediated transport of bile salts.31 This pump also influences drug absorption by modulating the production of bile salts. These combine with biliary cholesterol and phospholipids to form the micelles that facilitate the solubilization of drugs and their absorption by the intestine.

5.04.4.1.2 ABCC subfamily

Although P-gp is considered to be the major transporter responsible for drug export at the plasma membrane of many cells, MDR phenotypes that are not P-gp-mediated have been linked to several MRPs or ABCCs. The MRP subfamily of proteins was first described in 1992 when Cole and Deeley cloned ABCC1.32 Other MRPs followed in 1996, and several isoforms of the 12 members of the ABCC subfamily have now been found at various sites in the body. At least four of them, MRP2, 3, 4, 5, and recently MRP8, are likely to be involved in mediating drug resistance and to affect drug pharmacokinetics. Although several molecules are substrates of P-gp when the unconjugated cationic (vincristine and doxorubicin) and neutral (etoposide) compounds are transported, these MRPs preferentially transport anions (like many phase II metabolites of drugs) conjugated to GSH, glucuronate, or sulfate. The MRP4 and MRP5 proteins mainly confer resistance to cyclic nucleosides and purine analogs. They transport substrates by a different mechanism from P-gp; there may even be multiple mechanisms that include co-transport with GSH. All these isoforms are concentrated on specific areas of polarized cells, like the epithelial cells of the gut and kidney, and probably also in the brain microvessel endothelial cells. MRP2 and MRP4 are, like P-gp, found in the apical (luminal) membrane, while MRP1, MRP3, and MRP5 are found in the basolateral (abluminal) membrane.33,34

The 190-kDa MRP1 is the founding member of this subfamily. Despite its modest degree of sequence similarity with P-gp (approximately 15%), MRP1 confers similar degrees of resistance to anthracyclines, vinca alkaloids, camptothecins, and methotrexate, but not to taxanes, which are an important component of the P-gp profile. The substrate specificities of the two pumps differ markedly; MRP1 can transport lipophilic anions, including structurally diverse conjugates of GSH, glucuronate, and sulfate, such as the cysteinyl leukotriene LTC4, an important mediator of inflammatory responses, the estradiol 17^-D-glucuronide (E217^G), and sulfated bile acids. LTC4 is the substrate for which MRP1 has the highest affinity, with a Km of about 100 nM. The ability of MRP1 to transport GSH conjugates indicates that it is a ubiquitous GS-X pump.35 The precise mechanism by which GSH participates in MRPl-mediated efflux is still unsettled. At least four different mechanisms have been proposed.

The predominant idea is that GSH is a direct, low-affinity substrate for MRP1, or a co-substrate that allows the co-transport of substrates like vincristine, daunorubicin, and aflatoxin B1. Alternatively, GSH may stimulate the transport of certain compounds by MRP1, but is itself not translocated across the membrane. Conversely, GSH transport can be enhanced by certain substances, like verapamil, that are not themselves substrates of MRP1.35 Thus, the exact mechanism by which GSH is transported and interacts with MRP1 is quite complex. Although there are several potent inhibitors of P-gp, there are only a few inhibitors of MRP1. One of the more potent is the leukotriene antagonist MK571.36 Indomethacin and the isoflavonoid genestein have been reported to inhibit the transport function of MRP1 in vitro.37 Unfortunately, we have no specific inhibitors for each MRP homolog, so that it is quite possible to misinterpret results obtained using inhibitors in whole-cell systems that contain multiple isoforms of MRP.

The murine ortholog of MRP1, Mrp1, is 88% amino acid identical to human MRP1, but shows some differences in substrate specificity despite this great identity. Mouse and rat Mrp1 confer negligible resistance to anthracyclines compared with the human MRP1.38 Mrp1 ( — / — ) knockout mice were developed and found to be viable, healthy, and fertile, but they have altered immune responses that are attributed to decreased LTC4 secretion.39'40 Studies on Mrp1 ( — / — ) mice indicate that Mrp1 is involved in the defense against xenobiotics and the regulation of GSH. The GSH concentration is elevated in the tissues of Mrp1 ( — /— ) mice that normally contain high concentrations of Mrp1, whereas the GSH concentrations in tissues normally containing little Mrp1 are the same as in those of wild-type mice. The capacity of Mrp1 to function as an in vivo resistance factor is supported by the finding that Mrp1-deficient mice are hypersensitive to etoposide and the penetration of etoposide into the cerebrospinal fluid (CSF) is increased 10-fold resulting from the lack of Mrp1 at the choroid plexus.41

Prior to the identification of the MRP2 molecule, this protein was known as the canalicular multispecific organic anion transporter (cMOAT). MRP2 has 48% amino acid identity with MRP1 and lies at the apical membranes of epithelial cells. Its function was deduced from investigations in humans and rats that were genetically deficient in the pump.42 Dubin-Johnson syndrome, the Sprague-Dawley Eisai hyperbilirubinuric rat (EHBR), the Wistar transport deficient (TR—) rat, and Groningen yellow (GY) rats have all been used to assess the role of MRP2 in the excretion of conjugates in the bile.35 These rat strains have reduced biliary excretion of methotrexate and irinotecan.43 The drug resistance profile of MRP2 is similar to that of MRP1, but it is less potent. MRP2 also transports uncharged and cationic substrates such as saquinavir, rifampicin, sulfinpyrazone, and ceftriaxone, the flavonoids epicatechin (found in tea) and chrysin, and the meat-derived heterocyclic amine PhIP, a carcinogen with genotoxic properties.44 The MRP1 inhibitor MK-571 also blocks transport by MRP2. GSH plays a critical role in the MRP2-mediated transport of etoposide, vincristine, and vinblastine, as it does in MRP1, and GSH itself is actively transported into the bile by MRP2. Like MRP1, the transport protein has at least two binding sites that give rise to cooperative binding of substrates or modulators. Thus, the transport of E217^G is stimulated 30-fold by adding sulfamitran and sixfold by adding indomethacin.45

High concentrations of MRP2 mRNA are present in the human liver, and lower ones in the duodenum, brain, placenta, and kidney.46 These findings indicate that MRP2 plays a major role in the hepatobiliary excretion of drugs and conjugates. MRP2 is also an important component of the detoxification system of hepatocytes. Recent immunohistochemical and confocal microscopy studies showed that Mrp2 lies in the luminal membranes of the endothelial cells isolated from the brain capillaries of fish, rats, and pigs.47 This group also demonstrated that the luminal accumulation of the substrate sulforhodamine 101 was inhibited by other MRP substrates, implicating Mrp2 in the transport of drugs from the brain to blood. MRP2 has also been found in the luminal side of the human BBB and is overproduced in patients with resistant epilepsy.48 Potschka etal.49 showed that the concentrations of phenytoin and its anticonvulsant activity were significantly higher in the brains of Mrp2-deficient TR— rats than in normal rats. The authors suggest that MRP2 is involved, like P-gp, in the efflux of a wide spectrum of drugs, sometimes overlapping with that of P-gp. Thus MRP2 might play an important role in the detoxification and protection of the brain, similar to its action in hepatocytes. MRP2 is most abundant in the duodenum of rats and humans, and its concentration decreases toward the terminal ileum and colon, where there is very little. The production of MRP2 in the duodenum is inducible; it responds to signals from several nuclear receptors, including the retinoid X receptor (RXR), the retinoic acids receptor (RAR), and the farnesoid X receptor (FXR). FXR is also involved in bile acid homeostasis in the liver and gut.45

MRP3 is the human MRP that is most like MRP1, with 58% of amino acid identity. The concentration of MRP3 mRNA is high in the liver, duodenum, colon, and adrenal glands, and lower in the lung, kidney, bladder, spleen, and ovary.46'50 Despite the high concentration of MRP3 transcripts in the liver, the protein concentration is relatively low and MRP3 immunostaining is found in the bile duct epithelial cells and in the basolateral membrane of hepatocytes.46 The basolateral membranes of hepatocytes of cholestatic patients and those with Dubin-Johnson syndrome contain high concentrations of MRP3, suggesting that there is a compensatory induction of MRP3 in hepatocytes. MRP3 is mainly a GSH S-conjugate transporter that probably does not transport GSH itself. Its presence in hepatocytes and enterocytes indicates that MRP3 is involved in the enterohepatic circulation of nonsulfated and sulfated bile salts such as glycocholates and taurocholates. Thus MRP3 protects hepatocytes and enterocytes against endogenous bile salts and provides an efflux pump that can compensate for a deficient MRP2. The MRP3 substrate profile overlaps with that of MRP1 and MRP2, but the affinity of MRP3 and its capacity to produce drug resistance are not as great as those of either MRP1 or MRP2. MRP3 has a high affinity for glucuronidated compounds like etoposide-glucuronide, E217^G, and the glucuronides of morphine. A recent study demonstrated that Mrp3 ( — / — ) mice are unable to excrete morphine-3-glucuronide (M3G) from the liver into the bloodstream.51 This results in increased concentrations of M3G in the liver and bile and a 50-fold reduction in its plasma concentration. These data, plus the fact that the expression of MRP3 varies greatly from one human to another because of genetic variations and its induction by other compounds, raise questions about its function, particularly its influence on the differences in the pharmacokinetics and pharmacodynamics of morphine seen among individual patients.52,53

5.04.4.1.2.4 ABCC4 (MRP4, MOAT-B), ABCC5 (MRP5, MOAT-C), and ABCC8 (MRP8)

MRP1, 2, and 3 all have a third MSD, but MRP4, 5, and 8 do not (Figure 5). Thus their functions might be distinct from those of the previous members of the MRP family.

MRP4 and MRP5 do not confer resistance to anthracyclines or vinca alkaloids, but transport organic anions like typical MRP1 substrates (E217^G, methotrexate and reduced folates). Both pumps also selectively transport the nucleotides cAMP and cGMP, but the extent to which they influence cyclic nucleotide homeostasis seems to be limited by the highly efficient phosphodiesterase system, and they are probably more effective at mediating the extrusion of cAMP and cGMP.54 Certain nucleoside analogues, such as PMEA (9-(2-phosphonylmethoxyethyl adenine)), employed in the treatment of hepatitis B, and anticancer derivatives like 6-mercaptopurine (6MP) and 6-thioguanine, are also transported by both pumps. Neither transporter translocates uncharged purine and pyrimidine base analogues, but they do carry their metabolites. For example, 6MP is metabolized to its monophosphate intracellular cytotoxic metabolite, which is effluxed by MRP4 and MRP5. It remains to be determined whether these pumps are induced in treated patients, and if they contribute to the resistance of cells to the anticancer agents used in the maintenance therapy of childhood acute lymphoblastic leukemia or to antivirals such as PMEA and zalcitabine (ddc). GSH appears to be a substrate for both MRP4 and MRP5 and the co-transport of bile salts with GSH has been reported.55 However, the co-transport mechanism is not necessary for all substrates of MRP4.

MRP4 is found in the lung, kidney, bladder, liver, prostate, testis, ovary, and brain. Although the concentration in the liver appears to be low in most species, a recent study found MRP4/Mrp4 at the basolateral membrane in human, mouse and rat hepatocytes.56 Unlike MRP4, MRP5 is ubiquitous, with high concentrations of its mRNA in the brain, skeletal muscle, lung, and heart.46,50

The recent development of mrp4-deficient mice has shown that the anticancer drug topotecan, an Mrp4 substrate, accumulates in the brain parenchyma and CSF of these mice.57 Immunocytochemical analyses showed that Mrp4 is concentrated at the luminal membrane of the brain capillary endothelial cells and the basolateral membrane of the choroid plexus. This dual distribution of Mrp4 suggests that Mrp4 protects the brain from cytotoxins at both BBBs.

The human MRP8 (ABCC8) gene is very similar to MRP5 and is expressed in various tissues, including the liver and kidney. Like MRP4 and MRP5, MRP8 enhances the extrusion of cyclic nucleotides from cells and confers resistance to nucleoside analogues. LCT4, dehydroepiandrosterone sulfate (DHEAS), E217^G, monoanionic bile salts, and methotrexate were shown recently to be transported by MRP8.35

5.04.4.1.3 ABCG subfamily

The members of the ABCG subfamily differ from the more common ABC transporters, like P-gp and MRPs, in that they are half-transporters that are composed of a single NBD followed by one MSD with six transmembrane a-helices. The domains of P-gp and MRP1 are arranged in an opposite fashion, with the MSD followed by the NBD (Figure 5).

The second unique feature of the ABCG proteins is that they may work as homodimers or homo-oligomer or hetero-oligomer held together by disulfide bonds.

There are presently four known human members in the G subfamily: ABCG1, ABCG2, ABCG5, and ABCG8. They are all implicated in lipid transport, except ABCG2, which is important for drug resistance and drug disposition. This transporter was cloned independently by three different groups and called breast cancer resistance protein (BCRP), mitoxantrone-resistance protein (MXR), and placenta-specific ABC protein (ABCP), before it was designated ABCG2.58-60 This second member of the G subfamily confers resistance to anticancer agents by ensuring their energy-dependent efflux. The drug substrates include anthracyclines, mitoxantrone, the camptothecins, topotecan and irinotecan, and flavopiridol, a flavonoid-like cell cycle inhibitor, but not paclitaxel, cisplatin, or vinca alkaloids. BCRP also actively transports structurally diverse organic molecules, both conjugated and unconjugated, such as SN38, the metabolite of irinotecan and its glucuronide conjugate SN38-G, estrone-3-sulfate, 17b-E2G, DHEAS and organic anions like methotrexate.

Hence, BCRP seems to transport sulfated conjugates of steroids and xenobiotics rather than GSH and glucuronide metabolites. Other BCRP substrates include tyrosine kinase inhibitors like imatinib mesylate (Gleevec), which has also been proposed as a potent inhibitor of BCRP, nucleotide reverse transcriptase inhibitors, zidovudine (AZT), its active metabolite AZT5'-monophosphate, lamivudine (3TC), and the proton pump inhibitor pantoprazole.61 BCRP can transport chemical toxins, in addition to chemotherapeutic agents and conjugated or unconjugated organic anions. These chemicals include pheophorbide a, a breakdown product of dietary chlorophyll that is phototoxic, and the small heterocyclic amine carcinogen PhIP, which induces mammary and prostate cancers. Bcrpl-knockout mice suffer from diet-induced ear phototoxicity that results from accumulation of pheophorbide a in the brain. This occurs because these mice lack the Bcrpl needed to export pheophorbide a at both the intestine and BBB.62

The third-generation P-gp inhibitor, elacridar (GF120918), was recently found to be an efficient inhibitor of human BCRP and mouse Bcrp1. More specific BCRP inhibitors include the fungal toxin derivative fumitremorgin C (FTC); some analogs like KO143 are less toxic than FTC in vivo, but are more potent inhibitors than FTC. Several dietary flavonoids are also potent inhibitors of BCRP. Both 6-prenylchrysin and tectochrysin are more potent inhibitors than elacridar, and are promising new specific inhibitors for the reversal of ABCG2-mediated drug transport.63 BCRP is found in many hematological malignancies and solid tumors, where it confers resistance to chemotherapeutic agents. BCRP lies primarily in the plasma membrane and at the apical membrane of polarized epithelia, as does P-gp. High concentrations of BCRP are found in the placental syncytiotrophoblasts, the apical membrane of the epithelium of the small intestine, the liver canicular membrane, and at the luminal surface of the endothelial cells of the brain microvessels that form the BBB. Thus ABCG2 is found mainly in organs that are important for absorption (proximal part of the small intestine), distribution (placenta and the BBB), and elimination (liver and small intestine). Its tissue distribution overlaps considerably that of P-gp.21

Orally administered topotecan is much more bioavailable when it is given together with elacridar to either mice or humans. This is due to its more efficient intestinal uptake when BCRP is inhibited by elacridar, and its decreased hepatobiliary excretion since canalicular BCRP is also responsible for excretion into the bile.64 These data suggest that BCRP plays a major role in drug absorption and elimination.21 BCRP inhibitors might also be used to improve the penetration of BCRP anticancer drugs into the central nervous system (CNS). BCRP might be an important component of the efflux activity of the BBB. Recent studies of the P-gp and BCRP substrate imatinib in Bcrp1 knockout mice and Mdr1a and Mdr1b double-knockout mice show that BCRP, together with P-gp, is involved in the efflux of imatinib at the BBB.65 The chemotherapy treatment of primary or metastatic brain tumors could be improved by increasing the distribution of anticancer agents into the CNS by adding P-gp and BCRP inhibitors to the chemotherapy cocktail.21

BCRP has been found in stem cells and progenitor cells from the interstitial spaces of mammalian skeletal muscle, human pancreas islets, the human liver and heart, and the hematopoietic compartment.66 The BCRP in stem cells seems to protect them from cytotoxic substrates; this is consistent with the physiological role attributed to BCRP at other sites in the body. BCRP was also recently shown to secrete drugs or toxins into milk.67 BCRP lies in the apical membrane of the mammary gland alveolar epithelial cells, at the main site of milk production. It is present in the mammary glands of mice, cows, and humans and its concentration increases greatly during late pregnancy, and particularly during lactation in mice. The milk-to-plasma ratios of several drugs, such as aciclovir, cimetidine, and nitrofurantoin, were found to be high even before they were known to be BCRP substrates.68 Experimental studies with wild-type and Bcrp1 knockout mice have demonstrated that topotecan, the PhIP carcinogen and the hepatocarcinogen aflatoxin B1 become concentrated in milk.66 As the substrates transported by mouse and human BCRP are very similar, various types of compounds, such as drugs, pesticides, and carcinogens, are very likely to be concentrated in milk, placing infants and consumers of dairy products at risk of dangerously increased exposure. The secretion of xenobiotics into milk by BCRP is puzzling because this function exposes the suckling infant to a range of drugs and toxins. BCRP appears to protect against xenobiotics everywhere else in the body. Its physiological function in the mammary gland remains intriguing.

BCRP seems to have a large number of polymorphic variants, unlike other ABC proteins, and these may yield important functional differences. The first cloned BCRP cDNA was later found to encode a mutant BCRP that deviated from the 'wild type' BCRP at Arg 482 (R482); it was replaced by either threonine (R482T) or glycine (R482G). Mutations in BCRP alter its capacity to transport doxorubicin, rhodamine 123, topotecan, and methotrexate, but not the transport of mitoxantrone.69 However, these mutants have only been detected in cell lines overexpressing BCRP, and never in any normal human population or cancer specimens. Since the oral bioavaibility and clearance of drugs that are BCRP substrates, such as topotecan, varies greatly from one individual to another, analysis of the BCRP gene for SNPs can provide interesting data. Several mutations have been identified in the coding region of BCRP from healthy individuals and patients.69 Two of them, V12M and Q141 K, are polymorphic in several populations, with significant differences in allele frequencies between different populations around the world. The allele Q141 K is most frequent in Asian populations (approximately 30-60%) and relatively rare in Caucasians and African-Americans (approximately 5-10%). This variant of BCRP is less abundant at the plasma membrane of transfected cells, and therefore confers lower resistance to drugs than the wild-type protein.69,70 A recent clinical study correlated the Q141 K polymorphism with changes in the pharmacokinetic properties of diflomotecan. The plasma concentrations of diflomotecan in five heterozygote patients were much higher (299%) than those of 15 patients with wild-type alleles, while 11 known variants in the ABCB1, ABCC2, CYP3A4, and CYP3A5 genes did not affect diflomotecan disposition.71 Thus, BCRP can transport a structurally and functionally wide range of organic substrates, and this range overlaps extensively with those of P-gp, MRP1, and MRP2. The tissue distribution of BCRP varies greatly, but overlaps that of P-gp. We infer from this that BCRP has a very similar role to P-gp in the pharmacology and toxicology of substrates.

5.04.4.2 Solute Carrier Transporter Superfamily

While the transporters of the ABC superfamily are mainly concerned with the efflux of substrates from cells, the transporters of the second superfamily, the SLCs, are influx transporters. Unlike the ABC transporters, the physiological roles of which are seldom clearly understood, the SLC proteins are indispensable for the uptake of many essential nutrients by cells. They also play a critical role in the absorption, excretion and toxicity of many xenobiotics. Several inherited diseases, like the glucose-galactose and bile acid malabsorption syndromes, are attributed to mutations of SLC transporters.72,73

A total of 362 mammalian genes have, to date, been assigned to the SLC superfamily, divided into 46 families. The system for naming members of the SLC superfamily differs somewhat from the ABC nomenclature. The genes are usually named using the root symbol SLC, followed by a number corresponding to the family (e.g., SLC22, solute carrier family 22), the letter A, and finally the number of the individual transporter (e.g., SLC22A2). But there may be differences between families. The SLC21 family encoding the organic anion transporting proteins (OATPs) has been reclassified as a superfamily with families and subfamilies much like the classification of drug-metabolizing enzymes. The gene symbol then becomes SLCO (i.e., the '21' and the 'A' have been replaced by the letter 'O' for organic transporter) and the 'OATP' symbol has been kept for protein nomenclature (e.g., SLCO1A2 for the gene and OATP1A2 for the protein).

Tables 2-6 list the main characteristics of many of the SLC proteins implicated in pharmacology and toxicology. The SLC21 and SLC22 families contain several members that transport a variety of structurally diverse organic anions, cations, and uncharged compounds. Most of the members of the SLC21 family of OATPs transport anionic amphipathic compounds. The SLC22 family includes OCTs, the carnitine OCTs novel type (OCTNs), the urate anion-exchanger (URAT1), and several OATs. Other families that may be involved in pharmacology and toxicology include transporters with more restricted substrate specificities. These include the hexose transporters (SLC2 and SLC5), the amino acid (SLC7) transporters, which may be used for drug delivery, and the SLC16 that transport monocarboxylic acids. The main transporters include the SLC15 proteins that carry di- and tripeptides, and the SLC28 and SLC29 proteins that transport nucleoside analogues.

5.04.4.2.1 OATP (SLC21/SLCO) transporters

The nomenclature of the OATP is the most confusing of all the drug transporter families because different names have been coined for individual proteins and no orthologous human OATP genes have been identified for many rodent Oatp genes, indicating no one-to-one relationship between rodent Oatps and human OATPs. All Oatps/OATPs contain 12 TMDs; their structural features include a large extracellular domain between TMDs 9 and 10, N-glycosylation sites in

Table 2 Current human OATP protein, SLCO gene nomenclature and properties

Human gene name (old gene symbol)

Protein name

Common name (aliases)

Predominant substrates

Transport mode and energy source

Tissue distribution (cellular expression)

Predominant transport impact

Table 2 Current human OATP protein, SLCO gene nomenclature and properties

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