The organic anion transporting polypeptides (rodents: Oatps, human: OATPs) form a superfamily of sodium-independent transport systems that mediate the transmembrane transport of a wide range of ...amphipathic endogenous and exogenous organic compounds. Since the traditional SLC21 gene classification does not permit an unequivocal and species-independent identification of genes and gene products, all Oatps/OATPs are newly classified within the OATP/ SLCO superfamily and subdivided into families (>/=40% amino acid sequence identity), subfamilies (>/=60% amino acid sequence identity) and individual genes and gene products according to their phylogenetic relationships and chronology of identification. Implementation of this new classification and nomenclature system occurs in agreement with the HUGO Gene Nomenclature Committee (HGNC). Among 52 members of the OATP/ SLCO superfamily, 36 members have been identified so far in humans, rat and mouse. The latter are clustered within 6 (out of 12) families (OATP1-OATP6) and 13 subfamilies. Oatps/OATPs represent 12 transmembrane domain proteins and contain the superfamily signature D-X-RW-(I,V)-GAWW-X-G-(F,L)-L. Although species divergence, multispecificity and wide tissue distribution are common characteristics of many Oatps/OATPs, some members of the OATP/ SLCO superfamily are highly conserved during evolution, have a high substrate specificity and exhibit unique cellular expression in distinct organs. Hence, while Oatps/OATPs with broad substrate specificity appear to play an important role in the bioavailability, distribution and excretion of numerous exogenous amphipathic organic anionic compounds, Oatps/OATPs with a narrow spectrum of transport substrates may exhibit more specific physiological functions in distinct organs.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
The bile salt export pump Stieger, Bruno; Meier, Yvonne; Meier, Peter J
Pflügers Archiv,
02/2007, Volume:
453, Issue:
5
Journal Article
Peer reviewed
Open access
Canalicular secretion of bile salts mediated by the bile salt export pump Bsep constitutes the major driving force for the generation of bile flow. Bsep is a member of the B-family of the super ...family of ATP-binding cassette transporters and is classified as ABCB11. Bsep has a narrow substrate specificity, which is largely restricted to bile salts. Bsep is extensively regulated at the transcriptional and posttranscriptional level, which directly modulates canalicular bile formation. Pathophysiological alterations of Bsep by either inherited mutations or acquired processes such as inhibition by drugs or disease-related down regulation may lead to a wide spectrum of mild to severe forms of liver disease. Furthermore, many genetic variants of Bsep are known, some of which potentially render individuals susceptible to acquired forms of liver disease.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Organic anion transporting polypeptides (OATPs) are polyspecific organic anion transporters, which are expressed in the blood-brain barrier, the choroid plexus, and other organs. The physiologic ...function of OATPs in extrahepatic tissues remains ambiguous. In rat retina, members of the OATP family are expressed. We therefore investigated the human retina for the expression of OATP1A2 and OATP2B1 and extended the study to human brain. Furthermore, we searched for peptide neurotransmitters as novel OATP substrates. OATP1A2 displayed a broad expression pattern in human retina as assessed by immunofluorescence localization. It is expressed in photoreceptor bodies and somas of amacrine cells. OATP1B2 expression is restricted to the inner nuclear layer and to the inner plexiform layer. Using paraffin sections from human cortex, cerebellum, and hippocampus, OATP1A2 was localized to neurons and neuronal processes, while OATP2B1 is expressed in endothelial cells of brain capillaries. Substance P and vasoactive intestinal peptide were identified as substrates for OATP1A2 and OATP2B1. Double-labeling immunofluorescence of human retina demonstrated the presence of substance P and of vasoactive intestinal peptides in neurons expressing OATP1A2 and OATP2B1, respectively. The expression of OATP1A2 and OATP2B1 in retinal neurons implies a role of these transporters in the reuptake of peptide neurotransmitters released from retinal neurons. The abundant expression of OATP1A2 in brain neurons points to the possibility that OATP1A2 could be involved in the homeostasis of neurosteroids. The high expression of OATP2B1 in brain capillaries supports an important function of OATPs in substance penetration across the blood-brain barrier.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Drug‐induced liver injury is an important clinical problem with significant morbidity and mortality. Whereas for most hepatocellular forms of drug‐induced hepatic injury the underlying ...pathophysiological mechanism is poorly understood, there is increasing evidence that cholestatic forms of drug‐induced liver damage result from a drug‐ or metabolite‐mediated inhibition of hepatobiliary transporter systems. In addition to their key role in determining hepatic drug exposure and clearance, the coordinated action of these transport systems is essential for bile formation and the biliary secretion of cholephilic compounds and xenobiotics. Any drug‐mediated functional disturbance of these processes can lead to an intracellular accumulation of potentially harmful bile constituents and result in the development of cholestatic liver cell damage. In addition to direct drug‐mediated inhibition of hepatocellular transport, function of these transporters can be altered by pre‐existing hepatic disease and genetic factors, which contribute to the development of drug‐induced cholestasis in susceptible individuals. This review summarizes current knowledge about the function of hepatobiliary uptake and efflux systems and discusses factors that might predispose to drug‐induced cholestasis. (HEPATOLOGY 2006;44:778–787.)
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Intrahepatic cholestasis of pregnancy and drug-induced cholestasis are two clinically important forms of acquired cholestatic liver disease. The understanding of the underlying mechanisms of acquired ...cholestasis has recently made considerable progress by the identification of canalicular ATP-binding cassette (ABC) transporters as likely targets for these forms of cholestasis. Cholestasis of pregnancy is linked to estrogen and progesterone metabolites. These metabolites have been shown to impair the bile salt export pump (BSEP) function by an indirect mechanism. In addition, genetic variants (as well as mutants) of the genes coding for the phosphatidylcholine translocator MDR3 and BSEP and for the farnesoid X receptor, which is critical in the transcriptional activation of MDR3 ( ABCB4) and BSEP ( ABCB11) have been associated with intrahepatic cholestasis of pregnancy. The pathogenesis of drug-induced liver injury encompasses a wide spectrum of mechanisms, some of which are still poorly understood. BSEP is now known to be subject to drug inhibition in susceptible patients. Information on genetic factors rendering individuals susceptible to inhibition of BSEP by drugs or their metabolites is still scarce. Besides rare mutations that have been linked to drug-induced cholestasis, the common p.V444A polymorphism of BSEP has been identified as a potential risk factor. In this review, the authors summarize key concepts of physiology of bile formation, diagnostic principles to indentify these forms of acquired cholestasis, as well as pathogenetic mechanisms leading to intrahepatic cholestasis of pregnancy or drug-induced cholestasis. In addition, they review the current knowledge on genetic susceptibility factors for these two forms of cholestasis.
The vectorial transport of bile salts from blood into bile is essential for the generation of bile flow, solubilization of cholesterol in bile, and emulsification of lipids in the intestine. Major ...transport proteins involved in the enterohepatic circulation of bile salts include the hepatocellular bile salt export pump (BSEP, ABCB11), the apical sodium-dependent bile salt transporter (ASBT, SLC10A2) in cholangiocytes and enterocytes, the sodium-dependent hepatocyte bile salt uptake system NTCP (SLC10A1), the organic anion transporting polypeptides OATP-C (SLC21A6), OATP8 (SLC21A8) and OATP-A (SLC21A3), and the multidrug resistance protein MRP3 (ABCC3). Synthesis and transport of bile salts are intricately linked processes that undergo extensive feedback and feed-forward regulation by transcriptional and posttranscriptional mechanisms. A key regulator of hepatocellular bile salt homeostasis is the bile acid receptor/farnesoid X receptor FXR, which activates transcription of the BSEP and OATP8 genes and of the small heterodimer partner 1 (SHP). SHP is a transcriptional repressor that mediates bile acid-induced repression of the bile salt uptake systems rat Ntcp and human OATP-C. A nuclear receptor that activates rodent Oatp2 (Slc21a5) and human MRP2 (ABCC2) is the pregnane X receptor/steroid X receptor PXR/SXR. Intracellular trafficking and membrane insertion of bile salt transporters is regulated by lipid, protein, and extracellular signal-related kinases in response to physiologic stimuli such as cyclic adenosine monophosphate or taurocholate. Finally, dysfunction of individual bile salt transporters such as BSEP, on account of genetic mutations, steric inhibition, suppression of gene expression, or disturbed signaling, is an important cause of cholestatic liver disease.
Bile salt transporters Meier, Peter J; Stieger, B
Annual review of physiology,
01/2002, Volume:
64, Issue:
1
Journal Article
Peer reviewed
Bile salts are the major organic solutes in bile and undergo extensive enterohepatic circulation. Hepatocellular bile salt uptake is mediated predominantly by the Na(+)-taurocholate cotransport ...proteins Ntcp (rodents) and NTCP (humans) and by the Na(+)-independent organic anion-transporting polypeptides Oatp1, Oatp2, and Oatp4 (rodents) and OATP-C (humans). After diffusion (bound by intracellular bile salt-binding proteins) to the canalicular membrane, monoanionic bile salts are secreted into bile canaliculi by the bile salt export pump Bsep (rodents) or BSEP (humans). Both belong to the ATP-binding cassette (ABC) transporter superfamily. Dianionic conjugated bile salts are secreted into bile by the multidrug-resistance-associated proteins Mrp2/MRP2. In bile ductules, a minor portion of protonated bile acids and monomeric bile salts are reabsorbed by non-ionic diffusion and the apical sodium-dependent bile salt transporter Asbt/ASBT, transported back into the periductular capillary plexus by Mrp3/MRP3 and/or a truncated form of Asbt (tAsbt), and subjected to cholehepatic shunting. The major portion of biliary bile salts is aggregated into mixed micelles and transported into the intestine, where they are reabsorbed by apical Oatp3, the apical sodium-dependent bile salt transporter (ASBT), cytosolic intestinal bile acid-binding protein (IBABP), and basolateral Mrp3/MRP3 and tAsbt. Transcriptional and posttranscriptional regulation of these enterohepatic bile salt transporters is closely related to the regulation of lipid and cholesterol homeostasis. Furthermore, defective expression and function of bile salt transporters have been recognized as important causes for various cholestatic liver diseases.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
SUMMARY
Large-magnitude fluid-injection induced seismic events are a potential risk for geothermal energy developments worldwide. One potential risk mitigation measure is the application of cyclic ...injection schemes. After validation at small (laboratory) and meso (mine) scale, the concept has now been applied for the first time at field scale at the Pohang Enhanced Geothermal System (EGS) site in Korea.
From 7 August until 14 August 2017 a total of 1756 m³ of surface water was injected into Pohang well PX-1 at flow rates between 1 and 10 l s–1, with a maximum wellhead pressure (WHP) of 22.8 MPa, according to a site-specific cyclic soft stimulation schedule and traffic light system. A total of 52 induced microearthquakes were detected in real-time during and shortly after the injection, the largest of Mw 1.9. After that event a total of 1771 m³ of water was produced back from the well over roughly 1 month, during which time no larger-magnitude seismic event was observed. The hydraulic data set exhibits pressure-dependent injectivity increase with fracture opening between 15 and 17 MPa WHP, but no significant permanent transmissivity increase was observed.
The maximum magnitude of the induced seismicity during the stimulation period was below the target threshold of Mw 2.0 and additional knowledge about the stimulated reservoir was gained. Additionally, the technical feasibility of cyclic injection at field scale was evaluated. The major factors that limited the maximum earthquake magnitude are believed to be: limiting the injected net fluid volume, flowback after the occurrence of the largest induced seismic event, using a cyclic injection scheme, the application of a traffic light system, and including a prioriinformation from previous investigations and operations in the treatment design.
AIM： To study the association of three common ABCB11 and ABCC2 polymorphisms （ABCB11： 1331T〉C→V444A; ABCC2： 3563T〉A → V1188E and 4544G 〉A → C1515Y） with intrahepatic cholestasis of pregnancy （ICP） ...and contraceptive-induced cholestasis （CIC）. METHODS： ABCB11 and ABCC2 genotyping data were available from four CIC patients and from 42 and 33 ICP patients, respectively. Allele-frequencies of the studied polymorphisms were compared with those in healthy pregnant controls and Caucasian individuals. Furthermore, serum bile acid levels were correlated with the presence or absence of the 1331 C allele. RESULTS： The ABCB11 1331T〉C polymorphism was significantly more frequent in cholestatic patients than in pregnant controls： C allele 76.2% （CI, 58.0-94.4） vs 51.3% （CI 35.8-66.7）, respectively （P = 0.0007）; and CC allele 57.1% （CI 36.0-78.3） vs 20% （CI 7.6-32.4）, respectively （P = 0.0065）. All four CIC patients were homozygous carriers of the C allele. In contrast, none of the studied ABCC2 polymorphism was overrepresented in ICP or CIC patients. Higher serum bile acid levels were found in carriers of the 1331CC genotype compared to carriers of the TT genotype. CONCLUSION： Our data support a role for the ABCB11 1331T〉C polymorphism as a susceptibility factor for the development of estrogen-induced cholestasis, whereas no such association was found for ABCC2. Serum bile acid and 7-glutamyl transferase levels might help to distinguish ABCB4- and ABCB11-related forms of ICP and CIC.
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