ToxSci Advance Access originally published online on August 13, 2007
Toxicological Sciences 2008 101(2):186-196; doi:10.1093/toxsci/kfm214
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Xenobiotic Transporters: Ascribing Function from Gene Knockout and Mutation Studies
Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, 3901 Rainbow Building, Kansas City, Kansas 66160-7417
1 To whom correspondence should be addressed. Fax: (913) 588-7501. E-mail: cklaasse{at}kumc.edu.
Received June 18, 2007; accepted August 8, 2007
 |
ABSTRACT |
|---|
 TOP ABSTRACT INTRODUCTIONTRANSPORTERS IN INTESTINETRANSPORTERS IN LIVERTRANSPORTERS IN KIDNEYTRANSPORTERS IN OTHER TISSUESSUMMARYREFERENCES |
|---|
Transporter-mediated absorption, secretion, and reabsorption of chemicals are increasingly recognized as important determinants in the biological activities of many xenobiotics. In recent years, the rapid progress in generating and characterizing mice with targeted deletion of transporters has greatly increased our knowledge of the functions of transporters in the pharmacokinetics/toxicokinetics of xenobiotics. In this introduction, we focus on functions of transporters learned from experiments on knockout mice as well as humans and rodents with natural mutations of these transporters. We limit our discussion to transporters that either directly transport xenobiotics or are important in biliary excretion or cellular defenses, namely multidrug resistance, multidrug resistance–associated proteins, breast cancer resistance protein, organic anion transporting polypeptides, organic anion transporters, organic cation transporters, nucleoside transporters, peptide transporters, bile acid transporters, cholesterol transporters, and phospholipid transporters, as well as metal transporters. Efflux transporters in intestine, liver, kidney, brain, testes, and placenta can efflux xenobiotics out of cells and serve as barriers against the entrance of xenobiotics into cells, whereas many xenobiotics enter the biological system via uptake transporters. The functional importance of a given transporter in each tissue depends on its substrate specificity, expression level, and the presence/absence of other transporters with overlapping substrate preferences. Nevertheless, a transporter may affect a tissue independent of its local expression by altering systemic metabolism. Further studies on the gene regulation and function of transporters, as well as the interrelationship between transporters and phase I/II xenobiotic-metabolizing enzymes, will provide a complete framework for developing novel strategies to protect us from xenobiotic insults.
Key Words: transporter; function; xenobiotics; knockout; mice.
|
INTRODUCTION |
|---|
|
TOPABSTRACTINTRODUCTIONTRANSPORTERS IN INTESTINETRANSPORTERS IN LIVERTRANSPORTERS IN KIDNEYTRANSPORTERS IN OTHER TISSUESSUMMARYREFERENCES |
|---|
Lipophilic compounds are generally biotransformed by phase I and phase II metabolic enzymes into more water-soluble metabolites whose exit from the cells requires efflux transporters. Reactive species can be detoxified by phase II enzymes, such as glutathione-S-transferases, and the excretion of resultant conjugates also requires efflux transporters. Thus, efflux transporters are critical as a defense system to pump xenobiotics or their metabolites out of the body. The traditional thought is that chemicals, particularly lipophilic compounds, enter cells by passive diffusion. In recent years, with rapid progress in cloning and characterizing transporters, it is becoming evident that uptake transporters are essential in mediating the entrance of a large numbers of xenobiotics into cells. In this article, we attempt to provide a brief introduction on the biological functions of various efflux and uptake transporters. A prominent characteristic of these uptake and efflux transporters is the overlapping/multispecific substrate preferences. Thus, although many cellular studies have illustrated the compounds that transporters are able to transport in vitro, the functional importance of each transporter needs to be verified in vivo, in which the demonstration of function in knockout mice is the gold standard. Therefore, we will mainly introduce the knowledge on the biological functions of transporters that have been obtained from using knockout mice, although some knowledge from human mutations/polymorphisms and mutant rats will also be included. Our discussion will focus on roles of uptake and efflux transporters in the absorption, distribution, and excretion of endobiotics and xenobiotics in the intestine, liver, and kidney. A brief introduction on the roles of transporters in the blood-brain and blood-testis barriers will also be included. To have the maximum toxicological relevance in the shortest length, we will only include transporters that have direct roles in transporting xenobiotics or transporters that have profound effects on bile flow or intestinal absorption, which indirectly affect the absorption and/or disposition of xenobiotics.
|
TRANSPORTERS IN INTESTINE |
|---|
|
TOPABSTRACTINTRODUCTIONTRANSPORTERS IN INTESTINETRANSPORTERS IN LIVERTRANSPORTERS IN KIDNEYTRANSPORTERS IN OTHER TISSUESSUMMARYREFERENCES |
|---|
As the site of oral absorption, the intestine has high expression of various uptake transporters (Fig. 1) facilitating the absorption of structurally diverse substrates. Uptake transporters enriched on the apical membrane of enterocytes include peptide transporter 1 (Pept1, Slc15a1), concentrative nucleoside transporters (Cnt) Cnt1 (Slc28a1) and Cnt2 (Slc28a2), organic cation transporter n1 Octn1 (Slc22a4), organic anion transporting polypeptides (Oatp, Slco), cholesterol transporter Niemann-Pick C1-Like 1 (Npc1L1), apical sodium-dependent bile acid transporter (Asbt, Slc10a2), as well as divalent metal transporter 1 (Dmt1, Slc11a2). As the first barrier against xenobiotics, the intestine has high expression of efflux transporters on the apical membrane of enterocytes, including multidrug resistance 1 (Mdr1, Abcb1), multidrug resistance–associated protein 2 (Mrp2, Abcc2), breast cancer resistance protein (Bcrp, Abcg2), ATP-binding cassette (Abc) g5, and Abcg8. On the basolateral membrane of enterocytes, efflux transporters Mrp3 (Abcc3), organic solute transporter (Ost) alpha and beta, cholesterol transporter Abca1, and equilibrative nucleoside transporter 1 (Ent1, Slc29a1) are highly expressed.
|
Apical Uptake Transporters in Intestine
Pept1 is predominantly expressed in small intestine, responsible for intestinal absorption of di- and tri-peptides as well as various peptide-like drugs, including β-lactam antibiotics (e.g., penicillin, ceftibuten, and cefadroxil), angiotensin-converting enzyme inhibitors (e.g., captopril, enalapril, or benazepril), renin inhibitors (S 86,2033 and S 86,3390), thrombin inhibitors (e.g., CRC 220), the aminopeptidase inhibitor bestatin, and certain nonpeptidyl substrates (e.g., the monoamine oxidase inhibitor 4-aminophenylacetic acid, amino acid ester prodrugs of acyclovir, and zidovudine). Cnt1 and Cnt2 transport endogenous substrates such as adenosine, thymidine, cytidine, guanosine, uridine, inosine, and hypoxanthine. Cnts facilitate Na+-dependent uptake of nucleosides into cells against concentration gradients, with high affinity for their natural substrates. Cnt1 preferentially transports pyrimidine nucleosides; Cnt2 preferentially transports purine nucleosides. Many pharmaceutically important anticancer and antiviral drugs are nucleoside or nucleobase analogs; most of them are hydrophilic and cannot freely cross the plasma membrane. Thus, these drugs need nucleoside transporters for cellular uptake, such as 5-fluorouridine, 5-fluoro-2'-deoxyuridine, arabinosylcytosine, zidovudine, cladribine, diethyldithiocarbamate, 2',3'-dideoxyinosine, fludarabine, gemcitabine, melarsoprol, pentamidine, zalcitabine, and zebularine.
Octn1 is a pH-dependent and Na+-independent multispecific transporter-mediating transport of a variety of structurally diverse organic cations (e.g., desipramine, dimethylamiloride, cimetidine, procainamide, and verapamil). OATP1A2 (SLCO1A2) is present in human intestine (and Oatp2b1 in mouse intestine) and may be responsible for intestinal uptake of diverse chemicals; however, limited data are available regarding its relevance.
The cholesterol transporter Npc1L1 is enriched in the brush border membrane of enterocytes in the small intestine of humans and rodents. In humans, rare variants in NPC1L1 are associated with reduced sterol absorption and plasma low-density lipoprotein levels (Cohen et al., 2006
). Consistently, Npc1L1-null mice have a marked decrease in intestinal absorption of cholesterol and phytosterols (Altmann et al., 2004; Davis et al., 2004) and are completely resistant to diet-induced hypercholesterolemia (Davis et al., 2004). Thus, Npc1L1 is essential for intestinal uptake of both cholesterol and phytosterols and is important in cholesterol homeostasis. Ezetimibe, a drug used to treat hypercholesterolemia in patients, is an Npc1L1 inhibitor.
Bile acids play key roles in maintenance of bile flow, absorption of lipids, and disposition of lipophilic endobiotics and xenobiotics. Over 95% of bile acids secreted into bile are reabsorbed through highly regulated transport systems in liver and gastrointestinal tract. In humans, missense mutations of ASBT at conserved amino acid positions, L243P and T262M are associated with primary bile acid malabsorption (Oelkers et al., 1997). Studies in Asbt-null mice demonstrate that Asbt is essential for efficient intestinal absorption of bile acids (Dawson et al., 2003). Thus, inhibition of Asbt is a potential target for cholesterol-lowering drugs.
Studies in rats carrying a mutation in Dmt1 showed that it is essential for intestinal absorption of iron (Ferguson et al., 2003). Patients with DMT1 mutations have hypochromic anemia (Priwitzerova et al., 2005). DMT1 is an uptake transporter for Fe2+ and many other divalent metals such as Cd2+, Cu2+, Zn2+, Mn2+, Co2+, Ni2+, and Pb2+ but does not transport Fe3+; DMT1 is believed to mediate the absorption of lead and cadmium. Thus, intestinal induction of DMT1 during iron deficiency will increase the absorption of the toxic cadmium (Park et al., 2002).
Apical Efflux Transporters in Intestine
Mdr1, also known as P-glycoprotein, was the first identified efflux transporter due to its prominent role in mediating resistance of cancer cells to various cytotoxic anticancer drugs. Studies in Mdr1a/1b double-null mice demonstrate that Mdr1 at intestinal and blood-brain barriers critically protects against xenobiotics (Schinkel et al., 1997; Schinkel et al., 1995). Many therapeutically important drugs have been identified as Mdr1 substrates, such as vinblastine, paclitaxel, doxorubicin, etoposide, verapamil, digoxin, and cyclosporin A. Mdr1 inhibitors have been developed to overcome drug resistance of cancer cells; however, side effects of Mdr1 inhibition is a major obstacle to application of Mdr1 inhibitors in cancer chemotherapy.
Studies in both Eisai and TR-hyperbilirubinemic rats, which carry natural Mrp2 mutations, indicate that Mrp2 is responsible for the intestinal efflux of certain glucuronide metabolites (e.g., E3040, a novel thromboxane synthase inhibitor) (Adachi et al., 2005). Bcrp transports heme compounds and confers resistance to anticancer drugs (e.g., anthracyclines, mitoxantrone, and camptothecins). Bcrp-null mice are extremely sensitive to the dietary chlorophyll-breakdown product pheophorbide A, present in various plant-derived foods and food supplements. Defect in effluxing pheophorbide A in Bcrp-null mice results in severe, sometimes lethal phototoxic lesions on light-exposed skin (Jonker et al., 2002). Bcrp protects cells from hypoxia-induced injury through preventing intracellular accumulation of heme (Krishnamurthy et al., 2004), and Bcrp-null mice have protoporphyria (Jonker et al., 2002). Thus, subjects with low/absent BCRP activity may be at increased risk of developing protoporphyria and diet-dependent phototoxicity.
Abcg5 and Abcg8 are half transporters, forming heterodimers with each other to efflux phytosterols (plant sterols) and cholesterol out of intestine and liver. In patients with sitosterolemia (a rare inherited plant sterol storage disease), mutations in either ABCG5 or ABCG8 lead to increased blood concentration of phytosterols. Abcg5 and Abcg8 knockout mice have elevated blood levels of phytosterols and accumulate phytosterols in brain (Jansen et al., 2006). Selected dietary plant sterols disturb cholesterol homeostasis by affecting two critical regulatory pathways of lipid metabolism. Thus, Abcg5 and Abcg8 play a key role in protecting against disruption of cholesterol homeostasis by dietary plant sterols.
Basolateral Efflux Transporters in Intestine
Mrp3 has been shown to be able to transport certain bile acids; however, results from Mrp3-null mice showed that Mrp3 is not essential for intestinal reabsorption of bile acids (Belinsky et al., 2005). Instead, Ost
and Ostβ form heterodimers and transport major bile acids (Ballatori, 2005; Dawson et al., 2005). Thus, Ost and Ostβ are the putative bile acid transporters responsible for effluxing the reabsorbed bile acids back into the blood; nevertheless, the exact function of Ost in enterohepatic circulation of bile acids needs to be confirmed in knockout mice. Additionally, Abca1 is a cholesterol efflux transporter enriched on the basolateral membrane of enterocytes. Studies of Abca1-null mice showed that Abca1 is essential for intestinal absorption and whole-body metabolism of cholesterol (Drobnik et al., 2001). Additionally, the bidirectional nucleoside transporter Ent1 is proposed to be responsible for pumping the absorbed nucleosides back into blood; however, no in vivo data have been reported.
|
TRANSPORTERS IN LIVER |
|---|
|
TOPABSTRACTINTRODUCTIONTRANSPORTERS IN INTESTINETRANSPORTERS IN LIVERTRANSPORTERS IN KIDNEYTRANSPORTERS IN OTHER TISSUESSUMMARYREFERENCES |
|---|
In liver, uptake transporters play a key role in hepatic uptake and clearance of xenobiotics absorbed by the intestine, a process contributing to hepatic first pass. Uptake transporters expressed highly on the basolateral membrane of hepatocytes include the liver-specific bile acid transporter Na(+)-taurocholate cotransporting polypeptide (Ntcp, Slc10a1), liver-specific Oatp1b (OATP1B1 and 1B3 in humans and Oatp1b2 in rodents), Oatp1a (Oatp1a1 and 1a4 in rodents and OATP1A2 in human cholangiocytes), Oct1 (Slc22a1), organic anion transporter 2 (Oat2, Slc22a7), and Ent1 (Fig. 2). ATP8b1 is an aminophospholipid flippase localized to the apical membrane of hepatocytes and cholangiocytes. Canalicular transporters are responsible for biliary excretion of chemicals. Transporters expressed highly on the canalicular membrane include Mrp2, Bcrp, multidrug and toxin extrusion 1 (Mate1, Slc47a1), bile salt export pump (Bsep, Abcb11), Mdr2 (Abcb4), Abcg5, Abcg8, and ATP7b. Efflux transporters Mrp3, Mrp6 (Abcc6), and Abca1 are present at high levels on the basolateral membrane of hepatocytes, responsible for efflux of substrates back into the blood, a process called ‘retro-transport’.
|
Basolateral Uptake Transporters in Liver
Uptake studies demonstrate that a major portion of bile acid uptake by hepatocytes is Na+ dependent, and the liver-specific Ntcp transports all major bile acids (mainly conjugated bile acids) in a Na+-dependent manner. Thus, Ntcp is considered a major transporter responsible for hepatic uptake of bile acids. Nevertheless, Oatps are proposed to be responsible for the Na+-independent portion of uptake of bile acids into hepatocytes.
Oatps transport a wide variety of amphipathic organic compounds, such as bile acids, steroid conjugates, thyroid hormones, anionic oligopeptides, drugs, toxins, and other xenobiotics (Hagenbuch and Meier, 2004). However, different from MRP efflux transporters, the Oatp1a subfamily in rodents generally does not have orthologs in humans. Nevertheless, the rodent liver-specific basolateral uptake transporter Oatp1b2 (Slco1b2), previously known as Lst-1 or Oatp4, has the human orthologs OATP1B1 and OATP1B3 (Hagenbuch and Meier, 2004). In vitro studies show that phalloidin, a toxic bicyclic peptide from the toxic mushroom Amanita phalloides, is a specific substrate for rat Oatp1b2 as well as human OATP1B1 and OATP1B3 (Meier-Abt et al., 2004). Consistent with the in vitro studies, our in vivo study shows that Oatp1b2-null mice are completely resistant to phalloidin-induced hepatotoxicity; in contrast, Oatp1b2-null and wild-type mice are similarly susceptible to hepatotoxicity induced by -amanitin, a structurally similar bicyclic peptide responsible for the oral toxicity of Amanita phalloides in humans (Lu et al., unpublished results). Interestingly, in vitro studies indicate that the bile acid transporter Ntcp transports -amanitin (Gundala et al., 2004). Thus, Oatp1b2 and OATP1B1/1B3 appear to have unique substrate specificity and physiological functions in liver, and the bile acid transporter Ntcp may also be responsible for hepatic uptake of certain xenobiotics.
The polyspecific organic cation transporters Oct1, 2, and 3 transport various structurally diverse organic cations, including many drugs, toxins, and endogenous compounds; of them, only Oct1 is expressed at appreciable levels in liver. Consequently, relative to wild-type mice, Oct1-null mice have marked decreases in hepatic uptake of cationic compounds including tetraethylammonium (a model organic cation), anticancer drug metaiodobenzylguanidine, and the neurotoxin 1-methyl-4-phenylpyridium (Jonker et al., 2001).
The organic anion transporters Oat1-5 are predominantly expressed in renal proximal tubules; however, Oat2 (Slc22a7) is also expressed in liver and is thus postulated to be responsible for hepatic uptake of various organic anions, such as ochratoxin A and clinically important drugs (e.g., 5-fluorouracil and paclitaxel).
The bidirectional nucleoside transporter Ent1 (Slc29a1) is the only member of nucleoside transporters that is expressed at appreciable levels in mouse liver; however, the precise role of Ent1 in hepatic pathophysiology remains unknown.
Apical Flippase in Liver
Flippases are located in the membrane helping the movement of phospholipid molecules between the two leaflets that compose the plasma membrane. The flippase ATP8b1 translocates aminophospholipids from the outer to the inner leaflet of the apical membrane of hepatocytes and cholangiocytes. Humans with mutations in ATP8B1 develop type-1 progressive familial intrahepatic cholestasis (PFIC1). Interestingly, PFIC1 patients have hepatic downregulation of BSEP, which may partially explain the similar phenotypes between PFIC1 and PFIC2 (mutation in BSEP). ATP8b1-mutant mice have decreased biliary secretion of bile acids but increased biliary secretion of phosphatidylserine, cholesterol, and ectoenzymes (Paulusma et al., 2006).
Basolateral Efflux Transporters in Liver
Mrp3 has been shown to transport bile acids in vitro. After bile duct ligation, Mrp3-null mice have lower blood levels of bilirubin glucuronides and higher hepatic levels of bile acids relative to wild-type mice (Belinsky et al., 2005), indicating important roles of Mrp3 in retro-transporting bilirubin glucuronides and bile acids. Our previous studies showed that chemical induction of hepatic Mrp3 in rats markedly shifted the disposition of acetaminophen from biliary to urinary excretion (Gregus et al., 1990; Slitt et al., 2003). Conversely, Mrp3-null mice have markedly increased biliary excretion and decreased urinary excretion of acetaminophen and morphine glucuronides (Manautou et al., 2005; Zelcer et al., 2005). Thus, Mrp3 appears to play a key role in retro-transporting glucuronides from liver into blood and thus increasing their urinary excretion.
Mrp4 (Abcc4) is expressed highest in kidney and transports various substrates such as steroid glucuronides, folates, cAMP, cGMP, bile acids, and prostaglandins. Although the basal expression is low in liver, Mrp4 is induced in Mrp2-null mice and mice with cholestasis. After bile duct ligation, Mrp4-null mice have intrahepatic accumulation of bile acids and more severe liver injury (Mennone et al., 2006), indicating an important role of Mrp4 as a backup system to transport bile acids out of liver back into blood.
Mutations of the MRP6 (ABCC6) gene are implicated in the etiology of pseudoxanthoma elasticum and its vascular complications in humans. Mrp6-null mice develop mineralization of connective tissues, a phenotype similar to that in humans (Klement et al., 2005). Mrp6 transports small peptides such as the endothelin receptor antagonist BQ123. Interestingly, although Mrp6 mRNA and protein are expressed highest in liver, Mrp6-null mice do not have liver disease. It has been proposed that the complex disease pseudoxanthoma elasticum may be due to a metabolic disorder at the environment-genome interface.
Mice with hepatocyte-specific knockout of Abca1 have markedly decreased blood levels of total and high-density lipoproteins (HDL) cholesterol relative to wild-type mice, and Abca1-null hepatocytes lost apoA-I–dependent capacity of effluxing cholesterol and phospholipid, demonstrating a critical role of hepatic Abca1 in effluxing lipid into blood and in maintaining the circulation of mature HDL particles (Timmins et al., 2005).
Canalicular Efflux Transporters in Liver
Patients with Dubin-Johnson syndrome have mutations in MRP2 and resultant conjugated hyperbilirubinemia. It is generally accepted that reduced glutathione and most glutathione (GSH) conjugates of xenobiotics are excreted into bile by the MRP2-mediated pathway. Mrp2-null mice have a marked decrease in biliary excretion of reduced glutathione, but only a moderate decrease in bilirubin glucuronides, and they only develop mild hyperbilirubinemia (Vlaming et al., 2006). After oral administration, plasma values of the food-derived carcinogens 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) and 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) were 1.9- and 1.7-fold higher in Mrp2-null mice versus wild-type mice (Vlaming et al., 2006). Mrp2 was thought to mainly transport organic anions; however, a recent study in Mrp2-null mice shows that Mrp2 is essential in biliary excretion of paclitaxel, a highly lipophilic anticancer drug (Lagas et al., 2006), suggesting that Mrp2 may also be important in determining the pharmacokinetics of highly lipophilic anticancer drugs.
Sulfate and glucuronide conjugates are organic anions effectively excreted into bile by Mrp2 and Bcrp. In rats, sulfate and glucuronide conjugates are excreted into bile predominantly by Mrp2, whereas mouse Bcrp mediates biliary excretion of sulfate metabolites, and mouse Bcrp also plays a major role in biliary excretion of glucuronide metabolites (Zamek-Gliszczynski et al., 2006), which may explain the mild, rather than severe, hyperbilirubinemia in Mrp2-null mice.
The recently cloned transporter Mate1 is primarily expressed on the apical membrane of hepatic canaliculi and renal proximal tubules. Cellular studies show that Mate1 mediates H(+)-coupled electroneutral exchange of classical organic cations, such as tetraethylammonium and 1-methyl-4-phenylpyridinium (Otsuka et al., 2005). Thus, Mate1 appears to be the exporter for biliary and urinary excretion of cationic toxins.
Bsep is the primary bile acid efflux transporter responsible for biliary excretion of bile acids. Humans with BSEP mutations have severe PFIC2, and BSEP mutations are associated with hepatocellular carcinoma in young children (Knisely et al., 2006). However, Bsep-null mice have only moderate intrahepatic cholestasis; their biliary secretion of bile acids is 30% of normal (Wang et al., 2001), in contrast to <1% bile acid secretion in PFIC2 patients. In Bsep-null mice, relative to wild-type mice, biliary secretion of cholic acids dramatically decreases, and cholic acid feeding results in more severe cholestasis and liver injury (Wang et al., 2003). Further studies show that Mdr1, which is expressed at low levels in normal liver, is markedly induced in Bsep-null mice, and Mdr1 is able to transport bile acids in vitro with a fivefold lower affinity compared to Bsep (Lam et al., 2005). Consequently, mice with triple knockout of Bsep, Mdr1a, and Mdr1b develop severe cholestasis, liver injury, and liver cancer (unpublished results presented by Dr Victor Ling), similar to what have been observed in PFIC2 patients. These studies raise interesting questions on the putative species difference between humans and mice regarding gene regulation and/or function of the MDR1 P-glycoprotein; drugs that induce/activate MDR1 may ameliorate the severe liver disease in PFIC2 patients.
MDR3 (ABCB4) (and Mdr2 in rodents) is a phospholipid flippase translocating phospholipids from the inner to outer membrane of hepatocytes and cholangiocytes. In contrast to the role of Mdr1 in effluxing xenobiotics, MDR3/Mdr2 plays a key role in biliary excretion of cholesterol and lipids. Humans with MDR3 mutations develop PFIC3; a similar phenotype has been reproduced in Mdr2-null mice, manifested by the lack of biliary phospholipid excretion and development of progressive liver disease (de Vree et al., 1998). Gene knockout studies show that both Abcg5 and Abcg8 are essential for the biliary secretion of cholesterol (Klett et al., 2004). However, in Mdr2-null mice, Abcg5/g8 are unable to transport cholesterol into bile (Langheim et al., 2005), illustrating the intimate relationship between phospholipid and cholesterol secretion.
Copper is an essential trace element that plays a very important role in cell physiology. The Wilson disease gene ATP7b encodes a copper efflux transporter expressed predominantly in liver and to a lesser extent in most other tissues. Excess intracellular copper triggers the translocation of ATP7b protein from trans-Golgi network to the pericanalicular vesicles, where it sequesters copper in vesicles, which subsequently undergo exocytosis, releasing copper across the canalicular membrane (Cater et al., 2006). Humans with a mutated ATP7B have marked hepatic accumulation of copper and develop liver cirrhosis and neurological problems, which has been reproduced in ATP7b-null mice (Buiakova et al., 1999).
|
TRANSPORTERS IN KIDNEY |
|---|
|
TOPABSTRACTINTRODUCTIONTRANSPORTERS IN INTESTINETRANSPORTERS IN LIVERTRANSPORTERS IN KIDNEYTRANSPORTERS IN OTHER TISSUESSUMMARYREFERENCES |
|---|
Kidney plays a key role in urinary secretion and reabsorption of endogenous chemicals and/or xenobiotics, and is thus very rich in transporters (Fig. 3). Proximal tubules are the major site of secretion and reabsorption, where basolateral uptake transporters Oat1(Slc22a6), Oat3 (Slc22a8), Oct1, Oct2 (Slc22a2), and Oatp4c1 (Slco4c1) are responsible for transporting organic anions and cations from blood into tubular cells, whereas apical efflux transporters Mrp2, Mrp4, Mate1, Bcrp, and Mdr1 transport these organic anions and cations into urine for urinary secretion. On the apical membrane of proximal tubules, uptake transporters Oatp1a1, 1a4, 1a6, 2a1, 2b1, 3a1, Oat2 (Slc22a7), Oat5 (Slc22a10), urate transporter 1 (Urat1, Slc22a12), Octn1, Octn2 (Slc22a5), Cnt1, Pept2 (Slc15a2), Asbt, and type II Na(+)-Pi cotransporter (Npt2, Slc34a1) reabsorb chemicals filtered through glomeruli back into tubule cells, whereas basolateral efflux transporters Ost
, Ostβ, Mrp1 (Abcc1), Mrp3, Mrp5 (Abcc5), Mrp6, Ent1, and Ent2 transport these reabsorbed chemicals back into the blood.
|
Basolateral Uptake Transporters in Kidney
Oat1 and Oat3 are localized on the basolateral membrane, responsible for tubular uptake in renal proximal tubules. Despite the lack of morphological changes in Oat1-null and Oat3-null mice, there are considerable alterations in renal uptake and/or secretion of organic anions in these two knockout mice. In Oat1-null mice, loss of renal uptake of furosemide results in impaired diuretic responsiveness to this drug, and several endogenous organic anions display higher plasma concentrations and/or lower urinary concentrations (e.g., 3-hydroxyisobutyrate, 3-hydroxybutyrate, 4-hydroxyphenyllactate, benzoate, 2-hydroxy-3-methylvalerate, 3-hydroxypropionate, and N-acetylaspartate), suggesting the physiological role of Oat1 in transporting these compounds (Eraly et al., 2006
). Additionally, OAT1 has been implicated in renal uptake of 2,4-dichlorophenoxyacetate, an anionic herbicide, in humans (Nozaki et al., 2007). In Oat3-null mice, renal uptake of taurocholate, estrone sulfate, and para-aminohippurate are greatly decreased (Sweet et al., 2002).
Oct1 and Oct2 are localized to the basolateral membrane of proximal tubules, responsible for renal uptake of cationic compounds, and they have largely overlapping substrate specificities. Consequently, knockout of either Oct1 or Oct2 has minimal effect on urinary excretion of cationic chemicals; however, knockout of both Oct1 and Oct2 completely abolishes renal secretion of tetraethylammonium and substantially increases its blood concentration (Jonker et al., 2003).
Currently, Oatp4c1 is the only member of the Oatp family found to be expressed on the basolateral membrane of proximal tubules in humans and rodents. Oatp4c1 transports cardiac glycosides, thyroid hormone, cAMP, and methotrexate in vitro (Mikkaichi et al., 2004). Thus, Oatp4c1 may be important in transporting these chemicals into tubules.
Apical Efflux Transporters in Kidney
Mrp2 and Mrp4 are members of the Mrp family enriched on the apical membrane of proximal tubules, and they have overlapping substrate specificity. p-Aminohippurate (PAH) is the classical substrate used to characterize organic anion transport in kidney. Although both Mrp2 and Mrp4 are able to transport PAH, Mrp4 is expressed at higher levels and has higher affinity for PAH than Mrp2. Moreover, renal excretion of PAH in isolated perfused kidneys from wild-type and Mrp2-deficient TR– rats is not different (Smeets et al., 2004). Thus, relative to Mrp2, Mrp4 may play a more important role in renal secretion of certain organic anions. Mrp4 transports various substrates such as steroid glucuronides, folates, cAMP, cGMP, bile acids, and prostaglandins. Mrp4-null mice have lowered urinary excretion of diuretics (hydrochlorothiazide and furosemide) as well as antiviral drugs (adefovir and tenofovir) (Hasegawa et al., 2006; Imaoka et al., 2006).
Mate1, highly expressed in the proximal tubules, may be responsible for renal secretion of organic cations that are taken up into the proximal tubules by the basolateral Oct1 and Oct2 transporters. Bcrp is expressed at the highest levels in rodent kidney. In Bcrp-null mice, urinary excretion of 6-hydroxy-5,7-dimethyl-2-methylamino-4-(3-pyridylmethyl) benzothiazole (E3040, a thromboxane synthase inhibitor) decreased 60%, whereas urinary excretion of another sulfate, 4-methylumbelliferone sulfate, was not impaired (Mizuno et al., 2004). Thus, Bcrp is important in renal secretion of certain organic sulfates in mice; however, other transporters, such as Mrp2 and Mrp4, are also involved. It is noteworthy that although Bcrp is highly expressed in rodent kidneys, its expression is very low in human kidneys (Hilgendorf et al., 2007). Therefore, Bcrp may not be important in urinary excretion of xenobiotics in humans.
Renal expression of Mdr1 is restricted to the apical membrane of proximal tubules. P-glycoprotein substrates rhodamine 123 and digoxin accumulate in the proximal tubular epithelial cells of kidney from Mdr1a/1b(–)(–) mice (Tsuruoka et al., 2001), indicating the importance of Mdr1 in renal secretion of xenobiotics that are Mdr1 substrates.
Apical ReUptake Transporters in Kidney
Almost all the nutrients filtered through glomeruli need to be reabsorbed by apical uptake transporters. Oatps, such as Oatp1a1, 1a4, 1a6, 2a1, 2b1, and 3a1 may be responsible for reabsorption of organic anions. For example, it is proposed that the male-predominant renal expression of Oatp1a1 is responsible for the < 1% urinary clearance of 17β-estradiol glucuronide in male than in female rats (Gotoh et al., 2002). Oat2, Oat5, Oat-k1/k2, and the urate transporter Urat1, four members of the Oat family, are highly expressed on the apical membrane of renal proximal tubules in rodents. In vitro studies show that Oat5 transports the mycotoxin ochratoxin A, as well as endogenous chemicals such as estrone sulfate and dehydroepiandrosterone (Youngblood and Sweet, 2004). The kidney-specific transporters Oat-k1/k2 (identified in rats) transport various organic anions bidirectionally (Masuda, 2003); interestingly, they share 65.8% homology with human OATP1A2, which has wide tissue distribution. Urat1 is responsible for renal reabsorption of urate. Patients with idiopathic renal hypouricaemia have defects in URAT1 (Enomoto et al., 2002). The organic cation/carnitine transporter Octn2 is predominantly expressed in proximal tubules, responsible for renal reabsorption of carnitine and cationic drugs (e.g., verapamil, spironolactone, mildronate, and certain beta-lactam antibiotics); mutation of the Octn2 gene in humans and mice results in excessive urinary loss of carnitine, systemic carnitine deficiency, and disorder of fatty acid oxidation (Lahjouji et al., 2001). Cnt1 and Pept2 are responsible for tubular reabsorbance of nucleosides, di-/tri-peptides, and xenobiotics that are their structural analogs. In Pept2-null mice, renal reabsorption of glycylsarcosine, the prototypical Pept substrate, was almost abolished, resulting in lower systemic levels of glycylsarcosine (Ocheltree et al., 2005). Phosphate transporter Npt2 is expressed predominantly on the apical membrane of proximal tubules, responsible for renal reabsorption of filtered phosphate. Npt2-null mice have marked urinary elimination of phosphate, hypophosphatemia, and elevation in the blood levels of 1,25-dihydroxyvitamin D and calcium (Beck et al., 1998). Interestingly, Npt1, another member of the phosphate transporter, is able to transport beta-lactam antibiotics (e.g., benzylpenicillin, faropenem, and foscarnet). In rats, treatment with foscarnet (phosphonoformic acid), an Npt2 inhibitor, increases renal secretion of arsenate, the environmental contaminant structurally similar to phosphate (Csanaky and Gregus, 2001). Therefore, phosphate transporter Npt2/Npt1 may play important roles in renal reabsorption of arsenate and certain other xenobiotics.
Basolateral Efflux Transporters in Kidney
On the basolateral membrane of proximal tubules, Ost and Ostβ are the putative bile acid transporters responsible for pumping the reabsorbed bile acids (by Asbt) back into the blood. Mrp1, 3, 5, and 6 may transport organic anions from proximal tubules back into the blood; however, their exact function in the kidney awaits further investigation. Additionally, bidirectional nucleoside transporters Ent1 and Ent2 may transport the reabsorbed nucleosides back into the blood.
|
TRANSPORTERS IN OTHER TISSUES |
|---|
|
TOPABSTRACTINTRODUCTIONTRANSPORTERS IN INTESTINETRANSPORTERS IN LIVERTRANSPORTERS IN KIDNEYTRANSPORTERS IN OTHER TISSUESSUMMARYREFERENCES |
|---|
Apart from liver, kidney, and intestine, transporters also play important roles in the transport of endogenous chemicals and xenobiotics in blood-tissue barriers residing in the brain, testes, and placenta.
Transporters in Brain
Mdr1 (P-glycoprotein), expressed highly in the endothelial cells of brain capillaries, is a key component of the blood-brain barrier against xenobiotic insult to the brain. In the choroid plexus, Mrp1, Mrp4, and Pept2 are highly expressed (Choudhuri et al., 2003). Mrp1 transports conjugated organic anions (e.g., leukotriene C4 and GSH S-conjugates of prostaglandin A2) and cytotoxic hydrophobic peptides (de Jong et al., 2001). Mrp1 protects the choroid plexus epithelium and contributes to the blood-cerebrospinal fluid barrier (Wijnholds et al., 2000). In addition to choroid plexus, Mrp4 is also expressed in the apical membrane of endothelial cells of brain capillaries; Mrp4-null mice treated with the anticancer drug topotecan have increased levels of topotecan in the brain (Leggas et al., 2004). Pept2-null mice have a marked decrease in uptake of dipeptides into choroid plexus (Ocheltree et al., 2005; Shen et al., 2003). Additionally, Oat3 is moderately expressed in choroid plexus, and Oat3-null mice have a marked decrease in uptake of fluorescein in choroid plexus (Sweet et al., 2002).
In the brain, ethanol consumption decreases the expression of Ent1, which transports adenosine as well as nucleosides and nucleoside analogs. Ent1-null mice have decreased hypnotic and ataxic responses to ethanol and increased consumption of alcohol compared to their wild-type littermates; such phenotype is attenuated by an adenosine receptor agonist, indicating an important role of Ent1 in regulating adenosine signaling and ethanol consumption/behaviors in the brain (Choi et al., 2004).
Human OATP1C1 (SLCO1C1) and mouse Oatp1c1 proteins share 83.5% homology. Oatp1c1 has a high affinity and specificity for thyroxine (T4) and is expressed predominantly in capillaries throughout the brain (Tohyama et al., 2004). Thus, Oatp1c1 is proposed to be essential for transport of T(4) across the blood-brain barrier. The monocarboxylate transporter 8 (MCT8, SLC16A2) is a high-affinity transporter for the active hormone T3. Men with mutations in MCT8 have severe, X-linked, psychomotor retardation and high serum T3 levels (Friesema et al., 2006). A similar phenotype is replicated in Mct8-null mice, which have lower T3 in brain but higher T3 in liver, resulting in a decrease in serum cholesterol and an increase in alkaline phosphatase (Dumitrescu et al., 2006). Thus, chemicals affecting the expression/function of Oatp1c1 and Mct8 may alter thyroid hormone homeostasis and mental development.
Zinc is an essential trace element that plays a very important role in cellular functions. Zinc transporter 3 (Znt3, Slc30a3) resides on synaptic vesicle membranes of zinc-containing neurons; knockout of Znt3 eliminates zinc from synaptic vesicles in the intact mouse brain (Cole et al., 1999). Znt3-null mice have a marked decreased plaque load and less insoluble beta amyloid in the brain; thus, endogenous zinc transported by Znt3 may contribute to the accumulation of amyloid plaques in Alzheimer's disease (Lee et al., 2002).
Transporters in Testes
Mrp1 and Mrp9 are highly expressed in testes (Maher et al., 2005). Mrp1-null mice are susceptible to testicular damage induced by the anticancer drug etoposide phosphate (Wijnholds et al., 1998). Currently, the physiological function of the testis-specific Mrp9 remains unknown. The third organic cation/carnitine transporter Octn3 is almost exclusively expressed in testis; the physiological importance of Octn3 in the testis awaits further investigation. Additionally, members of the Oatp superfamily (Oatp6b1, Oatp6c1, and Oatp6d1) are exclusively expressed in testes (Suzuki et al., 2003); they are thought to be responsible for testicular uptake of dehydroepiandrosterone and its sulfates, precursors of in vivo androgen and, thus, estrogen biosynthesis.
Transporters in Placenta
Placental transporters play important roles in handling of xenobiotics across the maternal-fetal interface. In a study of placental expression of transporters, 16 transporters, namely Mdr1a and 1b, Mrp1 and 5, Oct3 and Octn1, Oatp1a5 (Slco1a5) and Oatp4a1 (Slco4a1), Dmt1, zinc transporter 1 (Znt1, Slc30a1), Atp7a, Atp7b, prostaglandin transporter, Abcg8, Ent1, and Ent2, are expressed in placenta at concentrations similar to or higher than in maternal liver and kidney in rats (Leazer and Klaassen, 2003). Additionally, Bcrp is highly expressed in human placenta and has been implicated as a placental survival factor (Evseenko et al., 2007). After intravenous administration of P-glycoprotein substrate drugs to the pregnant dams, Mdr1a/1b double-null fetuses have marked higher levels of digoxin, saquinavir, or paclitaxel than wild-type fetuses, indicating an essential role of Mdr1 in limiting fetal penetration of various potentially harmful or therapeutic compounds (Smit et al., 1999). Znt1-null mice die in utero, which cannot be rescued by manipulating maternal levels of zinc, indicating a key role of Znt1 in transplacental transporting maternal zinc into the embryonic environment (Andrews et al., 2004).
|
SUMMARY |
|---|
|
TOPABSTRACTINTRODUCTIONTRANSPORTERS IN INTESTINETRANSPORTERS IN LIVERTRANSPORTERS IN KIDNEYTRANSPORTERS IN OTHER TISSUESSUMMARYREFERENCES |
|---|
In recent years, the characterization of mice with targeted deletion of transporters has greatly increased our knowledge on the functional significance of transporters in toxicology. Efflux transporters in intestine, liver, kidney, brain, and testis serve as essential barriers against toxic xenobiotics, whereas many toxic xenobiotics enter the biological system via uptake transporters, such as phytosterols via NPC1L1, phalloidin via Oatp1b2, and heavy metals via DMT1. The functional importance of a given transporter in each tissue depends on its substrate specificity, expression level, and the presence/absence of other transporters with overlapping substrate preferences. Nevertheless, a transporter may affect a tissue, independent of its local expression by altering systemic metabolism, an example being MRP6 and pseudoxanthoma elasticum. Further studies on the gene regulation and function of transporters, as well as the interrelationship between transporters and phase I/II xenobiotic-metabolizing enzymes, will provide a complete framework for developing novel strategies to protect us from xenobiotic insults.
|
|
ACKNOWLEDGMENTS |
|---|
We thank Dr Xingguo Cheng for preparing diagrams used in this article.
|
REFERENCES |
|---|
|
TOPABSTRACTINTRODUCTIONTRANSPORTERS IN INTESTINETRANSPORTERS IN LIVERTRANSPORTERS IN KIDNEYTRANSPORTERS IN OTHER TISSUESSUMMARYREFERENCES |
|---|
Adachi Y, Suzuki H, Schinkel AH, Sugiyama Y. Role of breast cancer resistance protein (Bcrp1/Abcg2) in the extrusion of glucuronide and sulfate conjugates from enterocytes to intestinal lumen. Mol. Pharmacol. (2005) 67:923–928.
Altmann SW, Davis HR Jr., Zhu LJ, Yao X, Hoos LM, Tetzloff G, Iyer SP, Maguire M, Golovko A, Zeng M, et al. Niemann-Pick C1 Lik e 1 protein is critical for intestinal cholesterol absorption. Science (2004) 303:1201–1204.
Andrews GK, Wang H, Dey SK, Palmiter RD. Mouse zinc transporter 1 gene provides an essential function during early embryonic development. Genesis (2004) 40:74–81.[CrossRef][Web of Science][Medline]
Ballatori N. Biology of a novel organic solute and steroid transporter, Ostalpha-Ostbeta. Exp. Biol. Med. (Maywood) (2005) 230:689–698.
Beck L, Karaplis AC, Amizuka N, Hewson AS, Ozawa H, Tenenhouse HS. Targeted inactivation of Npt2 in mice leads to severe renal phosphate wasting, hypercalciuria, and skeletal abnormalities. Proc. Natl. Acad. Sci. USA (1998) 95:5372–5377.
Belinsky MG, Dawson PA, Shchaveleva I, Bain LJ, Wang R, Ling V, Chen ZS, Grinberg A, Westphal H, Klein-Szanto A, et al. Analysis of the in vivo functions of Mrp3. Mol. Pharmacol. (2005) 68:160–168.
Buiakova OI, Xu J, Lutsenko S, Zeitlin S, Das K, Das S, Ross BM, Mekios C, Scheinberg IH, Gilliam TC. Null mutation of the murine ATP7B (Wilson disease) gene results in intracellular copper accumulation and late-onset hepatic nodular transformation. Hum. Mol. Genet. (1999) 8:1665–1671.
Cater MA, La Fontaine S, Shield K, Deal Y, Mercer JF. ATP7B mediates vesicular sequestration of copper: Insight into biliary copper excretion. Gastroenterology (2006) 130:493–506.[CrossRef][Web of Science][Medline]
Choi DS, Cascini MG, Mailliard W, Young H, Paredes P, McMahon T, Diamond I, Bonci A, Messing RO. The type 1 equilibrative nucleoside transporter regulates ethanol intoxication and preference. Nat. Neurosci. (2004) 7:855–861.[CrossRef][Web of Science][Medline]
Choudhuri S, Cherrington NJ, Li N, Klaassen CD. Constitutive expression of various xenobiotic and endobiotic transporter mRNAs in the choroid plexus of rats. Drug Metab. Dispos. (2003) 31:1337–1345.
Cohen JC, Pertsemlidis A, Fahmi S, Esmail S, Vega GL, Grundy SM, Hobbs HH. Multiple rare variants in NPC1L1 associated with reduced sterol absorption and plasma low-density lipoprotein levels. Proc. Natl. Acad. Sci. USA (2006) 103:1810–1815.
Cole TB, Wenzel HJ, Kafer KE, Schwartzkroin PA, Palmiter RD. Elimination of zinc from synaptic vesicles in the intact mouse brain by disruption of the ZnT3 gene. Proc. Natl. Acad. Sci. USA (1999) 96:1716–1721.
Csanaky I, Gregus Z. Effect of phosphate transporter and methylation inhibitor drugs on the disposition of arsenate and arsenite in rats. Toxicol. Sci. (2001) 63:29–36.
Davis HR Jr., Zhu LJ, Hoos LM, Tetzloff G, Maguire M, Liu J, Yao X, Iyer SP, Lam MH, Lund EG, et al. Niemann-Pick C1 Like 1 (NPC1L1) is the intestinal phytosterol and cholesterol transporter and a key modulator of whole-body cholesterol homeostasis. J. Biol. Chem. (2004) 279:33586–33592.
Dawson PA, Haywood J, Craddock AL, Wilson M, Tietjen M, Kluckman K, Maeda N, Parks JS. Targeted deletion of the ileal bile acid transporter eliminates enterohepatic cycling of bile acids in mice. J. Biol. Chem. (2003) 278:33920–33927.
Dawson PA, Hubbert M, Haywood J, Craddock AL, Zerangue N, Christian WV, Ballatori N. The heteromeric organic solute transporter alpha-beta, Ostalpha-Ostbeta, is an ileal basolateral bile acid transporter. J. Biol. Chem. (2005) 280:6960–6968.
de Jong MC, Slootstra JW, Scheffer GL, Schroeijers AB, Puijk WC, Dinkelberg R, Kool M, Broxterman HJ, Meloen RH, Scheper RJ. Peptide transport by the multidrug resistance protein MRP1. Cancer Res. (2001) 61:2552–2557.
de Vree JM, Jacquemin E, Sturm E, Cresteil D, Bosma PJ, Aten J, Deleuze JF, Desrochers M, Burdelski M, Bernard O, et al. Mutations in the MDR3 gene cause progressive familial intrahepatic cholestasis. Proc. Natl. Acad. Sci. USA (1998) 95:282–287.
Drobnik W, Lindenthal B, Lieser B, Ritter M, Christiansen Weber T, Liebisch G, Giesa U, Igel M, Borsukova H, Buchler C, et al. ATP-binding cassette transporter A1 (ABCA1) affects total body sterol metabolism. Gastroenterology (2001) 120:1203–1211.[CrossRef][Web of Science][Medline]
Dumitrescu AM, Liao XH, Weiss RE, Millen K, Refetoff S. Tissue-specific thyroid hormone deprivation and excess in monocarboxylate transporter (mct) 8-deficient mice. Endocrinology (2006) 147:4036–4043.
Enomoto A, Kimura H, Chairoungdua A, Shigeta Y, Jutabha P, Cha SH, Hosoyamada M, Takeda M, Sekine T, Igarashi T, et al. Molecular identification of a renal urate anion exchanger that regulates blood urate levels. Nature (2002) 417:447–452.[Medline]
Eraly SA, Vallon V, Vaughn DA, Gangoiti JA, Richter K, Nagle M, Monte JC, Rieg T, Truong DM, Long JM, et al. Decreased renal organic anion secretion and plasma accumulation of endogenous organic anions in OAT1 knock-out mice. J. Biol. Chem. (2006) 281:5072–5083.
Evseenko DA, Murthi P, Paxton JW, Reid G, Emerald BS, Mohankumar KM, Lobie PE, Brennecke SP, Kalionis B, Keelan JA. The ABC transporter BCRP/ABCG2 is a placental survival factor, and its expression is reduced in idiopathic human fetal growth restriction. Faseb J. (2007) Doi:10.1096/fj.07-8688com.
Ferguson CJ, Wareing M, Delannoy M, Fenton R, McLarnon SJ, Ashton N, Cox AG, McMahon RF, Garrick LM, Green R, et al. Iron handling and gene expression of the divalent metal transporter, DMT1, in the kidney of the anemic Belgrade (b) rat. Kidney Int. (2003) 64:1755–1764.[CrossRef][Web of Science][Medline]
Friesema EC, Jansen J, Heuer H, Trajkovic M, Bauer K, Visser TJ. Mechanisms of disease: Psychomotor retardation and high T3 levels caused by mutations in monocarboxylate transporter 8. Nat. Clin. Pract. Endocrinol. Metab. (2006) 2:512–523.[CrossRef][Web of Science][Medline]
Glaeser H, Bailey DG, Dresser GK, Gregor JC, Schwarz UI, McGrath JS, Jolicoeur E, Lee W, Leake BF, Tirona RG, et al. Intestinal drug transporter expression and the impact of grapefruit juice in humans. Clin. Pharmacol. Ther. (2007) 81:362–370.[CrossRef][Web of Science][Medline]
Gotoh Y, Kato Y, Stieger B, Meier PJ, Sugiyama Y. Gender difference in the Oatp1-mediated tubular reabsorption of estradiol 17beta-D-glucuronide in rats. Am. J. Physiol. Endocrinol. Metab. (2002) 282:E1245–E1254.
Gregus Z, Madhu C, Klaassen CD. Effect of microsomal enzyme inducers on biliary and urinary excretion of acetaminophen metabolites in rats. Decreased hepatobiliary and increased hepatovascular transport of acetaminophen-glucuronide after microsomal enzyme induction. Drug Metab. Dispos. (1990) 18:10–19.[Abstract]
Gundala S, Wells LD, Milliano MT, Talkad V, Luxon BA, Neuschwander-Tetri BA. The hepatocellular bile acid transporter Ntcp facilitates uptake of the lethal mushroom toxin alpha-amanitin. Arch. Toxicol. (2004) 78:68–73.[CrossRef][Web of Science][Medline]
Hagenbuch B, Meier PJ. Organic anion transporting polypeptides of the OATP/ SLC21 family: Phylogenetic classification as OATP/ SLCO superfamily, new nomenclature and molecular/functional properties. Pflugers Arch. (2004) 447:653–665.[CrossRef][Web of Science][Medline]
Hasegawa M, Kusuhara H, Adachi M, Schuetz JD, Takeuchi K, Sugiyama Y. Multidrug resistance-associated protein 4 is involved in the urinary excretion of hydrochlorothiazide and furosemide. J. Am. Soc. Nephrol. (2007) 18:37–45.
Hilgendorf C, Ahlin G, Seithel A, Artursson P, Ungell AL, Karlsson J. Expression of thirty-six drug transporter genes in human intestine, liver, kidney, and organotypic cell lines. Drug Metab. Dispos. (2007) 35:1333–1340.
Imaoka T, Kusuhara H, Adachi M, Schuetz JD, Takeuchi K, Sugiyama Y. Functional involvement of multidrug resistance associated protein 4 (MRP4/ABCC4) in the renal elimination of the anti-viral drugs, adefovir and tenofovir. Mol. Pharmacol. (2007) 71:619–627.
Jansen PJ, Lutjohann D, Abildayeva K, Vanmierlo T, Plosch T, Plat J, von Bergmann K, Groen AK, Ramaekers FC, Kuipers F, et al. Dietary plant sterols accumulate in the brain. Biochim. Biophys. Acta (2006) 1761:445–453.[Medline]
Jonker JW, Buitelaar M, Wagenaar E, Van Der Valk MA, Scheffer GL, Scheper RJ, Plosch T, Kuipers F, Elferink RP, Rosing H, et al. The breast cancer resistance protein protects against a major chlorophyll-derived dietary phototoxin and protoporphyria. Proc. Natl. Acad. Sci. USA (2002) 99:15649–15654.
Jonker JW, Wagenaar E, Mol CA, Buitelaar M, Koepsell H, Smit JW, Schinkel AH. Reduced hepatic uptake and intestinal excretion of organic cations in mice with a targeted disruption of the organic cation transporter 1 (Oct1 [Slc22a1]) gene. Mol. Cell. Biol. (2001) 21:5471–5477.
Jonker JW, Wagenaar E, Van Eijl S, Schinkel AH. Deficiency in the organic cation transporters 1 and 2 (Oct1/Oct2 [Slc22a1/Slc22a2]) in mice abolishes renal secretion of organic cations. Mol. Cell. Biol. (2003) 23:7902–7908.
Klement JF, Matsuzaki Y, Jiang QJ, Terlizzi J, Choi HY, Fujimoto N, Li K, Pulkkinen L, Birk DE, Sundberg JP, et al. Targeted ablation of the abcc6 gene results in ectopic mineralization of connective tissues. Mol. Cell. Biol. (2005) 25:8299–8310.
Klett EL, Lu K, Kosters A, Vink E, Lee MH, Altenburg M, Shefer S, Batta AK, Yu H, Chen J, et al. A mouse model of sitosterolemia: Absence of Abcg8/sterolin-2 results in failure to secrete biliary cholesterol. BMC Med. (2004) 2:5.[CrossRef][Medline]
Knisely AS, Strautnieks SS, Meier Y, Stieger B, Byrne JA, Portmann BC, Bull LN, Pawlikowska L, Bilezikci B, Ozcay F, et al. Hepatocellular carcinoma in ten children under five years of age with bile salt export pump deficiency. Hepatology (2006) 44:478–486.[CrossRef][Web of Science][Medline]
Krishnamurthy P, Ross DD, Nakanishi T, Bailey-Dell K, Zhou S, Mercer KE, Sorrentino BP, Schuetz JD. The stem cell marker Bcrp/ABCG2 enhances hypoxic cell survival through interactions with heme. J. Biol. Chem. (2004) 279:24218–24225.
Lagas JS, Vlaming ML, van Tellingen O, Wagenaar E, Jansen RS, Rosing H, Beijnen JH, Schinkel AH. Multidrug resistance protein 2 is an important determinant of paclitaxel pharmacokinetics. Clin. Cancer Res. (2006) 12:6125–6132.
Lahjouji K, Mitchell GA, Qureshi IA. Carnitine transport by organic cation transporters and systemic carnitine deficiency. Mol. Genet. Metab. (2001) 73:287–297.[CrossRef][Web of Science][Medline]
Lam P, Wang R, Ling V. Bile acid transport in sister of P-glycoprotein (ABCB11) knockout mice. Biochemistry (2005) 44:12598–12605.[CrossRef][Web of Science][Medline]
Langheim S, Yu L, von Bergmann K, Lutjohann D, Xu F, Hobbs HH, Cohen JC. ABCG5 and ABCG8 require MDR2 for secretion of cholesterol into bile. J. Lipid Res. (2005) 46:1732–1738.
Leazer TM, Klaassen CD. The presence of xenobiotic transporters in rat placenta. Drug Metab. Dispos. (2003) 31:153–167.
Lee JY, Cole TB, Palmiter RD, Suh SW, Koh JY. Contribution by synaptic zinc to the gender-disparate plaque formation in human Swedish mutant APP transgenic mice. Proc. Natl. Acad. Sci. USA (2002) 99:7705–7710.
Leggas M, Adachi M, Scheffer GL, Sun D, Wielinga P, Du G, Mercer KE, Zhuang Y, Panetta JC, Johnston B, et al. Mrp4 confers resistance to topotecan and protects the brain from chemotherapy. Mol. Cell. Biol. (2004) 24:7612–7621.
Maher JM, Slitt AL, Cherrington NJ, Cheng X, Klaassen CD. Tissue distribution and hepatic and renal ontogeny of the multidrug resistance-associated protein (Mrp) family in mice. Drug Metab. Dispos. (2005) 33:947–955.
Manautou JE, de Waart DR, Kunne C, Zelcer N, Goedken M, Borst P, Elferink RO. Altered disposition of acetaminophen in mice with a disruption of the Mrp3 gene. Hepatology (2005) 42:1091–1098.[CrossRef][Web of Science][Medline]
Masuda S. Functional characteristics and pharmacokinetic significance of kidney-specific organic anion transporters, OAT-K1 and OAT-K2, in the urinary excretion of anionic drugs. Drug Metab. Pharmacokinet. (2003) 18:91–103.[CrossRef][Medline]
Meier-Abt F, Faulstich H, Hagenbuch B. Identification of phalloidin uptake systems of rat and human liver. Biochim. Biophys. Acta (2004) 1664:64–69.[Medline]
Meier Y, Eloranta JJ, Darimont J, Ismair MG, Hiller C, Fried M, Kullak-Ublick GA, Vavricka SR. Regional distribution of solute carrier mRNA expression along the human intestinal tract. Drug Metab. Dispos. (2007) 35:590–594.
Mennone A, Soroka CJ, Cai SY, Harry K, Adachi M, Hagey L, Schuetz JD, Boyer JL. Mrp4-/- mice have an impaired cytoprotective response in obstructive cholestasis. Hepatology (2006) 43:1013–1021.[CrossRef][Web of Science][Medline]
Mikkaichi T, Suzuki T, Onogawa T, Tanemoto M, Mizutamari H, Okada M, Chaki T, Masuda S, Tokui T, Eto N, et al. Isolation and characterization of a digoxin transporter and its rat homologue expressed in the kidney. Proc. Natl. Acad. Sci. USA (2004) 101:3569–3574.
Mizuno N, Suzuki M, Kusuhara H, Suzuki H, Takeuchi K, Niwa T, Jonker JW, Sugiyama Y. Impaired renal excretion of 6-hydroxy-5, 7-dimethyl-2-methylamino-4-(3-pyridylmethyl) benzothiazole (E3040) sulfate in breast cancer resistance protein (BCRP1/ABCG2) knockout mice. Drug Metab. Dispos. (2004) 32:898–901.
Nozaki Y, Kusuhara H, Kondo T, Hasegawa M, Shiroyanagi Y, Nakazawa H, Okano T, Sugiyama Y. Characterization of the uptake of organic anion transporter (OAT) 1 and OAT3 substrates by human kidney slices. J. Pharmacol. Exp. Ther. (2007) 321:362–369.
Ocheltree SM, Shen H, Hu Y, Keep RF, Smith DE. Role and relevance of peptide transporter 2 (PEPT2) in the kidney and choroid plexus: In vivo studies with glycylsarcosine in wild-type and PEPT2 knockout mice. J. Pharmacol. Exp. Ther. (2005) 315:240–247.
Oelkers P, Kirby LC, Heubi JE, Dawson PA. Primary bile acid malabsorption caused by mutations in the ileal sodium-dependent bile acid transporter gene (SLC10A2). J. Clin. Investig. (1997) 99:1880–1887.[Web of Science][Medline