Bile acid transporters and regulatory nuclear receptors in the liver and beyond

Halilbasic, Emina; Claudel, Thierry; Trauner, Michael

doi:10.1016/j.jhep.2012.08.002

Cited by 320 publications

(286 citation statements)

References 161 publications

(146 reference statements)

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“…Gadoxetic acid enters the hepatocytes via active transport by OATP1B1/3 and is excreted into the biliary tree via MRP2 (23,28). Organic acid efflux from hepatocytes may also occur through the sinusoidal membrane because of bidirectional transport with OATP1B1/3 and MRP3 (23,28). We found that OATP1B1/3 expression was the main determinant responsible for uptake of gadoxetic acid in HCAs (P , .001).…”

Section: Gastrointestinal Imaging: Hepatocellular Adenoma With Gadoxementioning

confidence: 75%

“…It is well known that gadoxetic acid movement in hepatocytes is mediated by various transporters located on either the sinusoidal (OATP1B1/3 and MRP3) or canalicular (MRP2) membranes of the cell (19,22,32). Gadoxetic acid enters the hepatocytes via active transport by OATP1B1/3 and is excreted into the biliary tree via MRP2 (23,28). Organic acid efflux from hepatocytes may also occur through the sinusoidal membrane because of bidirectional transport with OATP1B1/3 and MRP3 (23,28).…”

Section: Gastrointestinal Imaging: Hepatocellular Adenoma With Gadoxementioning

confidence: 99%

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Morphologic and Molecular Features of Hepatocellular Adenoma with Gadoxetic Acid–enhanced MR Imaging

Ba‐Ssalamah¹,

Antunes

Feier³

et al. 2015

Radiology

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102

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Purpose:To evaluate the diagnostic performance of imaging features of gadoxetic acid-enhanced magnetic resonance (MR) imaging to differentiate among hepatocellular adenoma (HCA) subtypes by using the histopathologic results of the new immunophenotype and genotype classification and to correlate the enhancement pattern on the hepatobiliary phase (HBP) with the degrees of expression of organic anion transporting polypeptide (OATP1B1/3), multidrug resistance-associated protein 2 (MRP) (MRP2), and MRP 3 (MRP3) transporters. Materials and Methods:This retrospective study was approved by the institutional review board, and the requirement for informed consent waived. MR imaging findings of 29 patients with 43 HCAs were assessed by two radiologists independently then compared with the histopathologic analysis as the standard of reference. Receiver operating characteristic curves and Spearman rank correlation coefficient were used to test the diagnostic performance of gadoxetic acid-enhanced MR imaging features, which included the retention or washout at HBP and degree of transporter expression. Interreader agreement was assessed by using the k statistic with 95% confidence interval. Results:The area under the curve for the diagnosis of inflammatory HCA was 0.79 (95% confidence interval: 0.64, 0.90); for the steatotic type, it was 0.90 (95% confidence interval: 0.77, 0.97); and for the b-catenin type, it was 0.87 (95% confidence interval: 0.74, 0.95). There were no imaging features that showed a significant statistical correlation for the diagnosis of unclassified HCAs. On immunohistochemical staining, OATP1B1/3 expression was the main determinant for the retention, whereas MRP3 was the key determinant for washout of gadoxetic acid at HBP (P , .001). MRP2 appeared to have no role. Conclusion:Gadoxetic acid-enhanced MR imaging features may suggest the subtype of HCA. The degree of OATP1B1/3 and MRP3 expression correlated statistically with gadoxetic acid retention and washout, respectively, in the HBP.q RSNA, 2015

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Section: Gastrointestinal Imaging: Hepatocellular Adenoma With Gadoxementioning

confidence: 75%

Section: Gastrointestinal Imaging: Hepatocellular Adenoma With Gadoxementioning

confidence: 99%

Morphologic and Molecular Features of Hepatocellular Adenoma with Gadoxetic Acid–enhanced MR Imaging

Ba‐Ssalamah¹,

Antunes

Feier³

et al. 2015

Radiology

Self Cite

102

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“…Bile acid transporters, namely, BSEP, NTCP, and MRP 2 , play a key role in bile acid homeostasis (39,40), while inhibition of the bile acid transporters BSEP and NTCP was suggested to participate in INH-induced liver injury pathogenesis (41). Our preceding study (22) showed that the INH-LPS combination elevated the expression of the bile acid-synthesizing enzyme (CYP7A1) while the expression of transporters (BSEP, NTCP, and MRP 2 ) was significantly reduced.…”

Section: Discussionmentioning

confidence: 95%

Role of Inflammatory and Oxidative Stress, Cytochrome P450 2E1, and Bile Acid Disturbance in Rat Liver Injury Induced by Isoniazid and Lipopolysaccharide Cotreatment

Hassan

Guo

Yousef

et al. 2016

Antimicrob Agents Chemother

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Isoniazid (INH), since its introduction in the year 1952, still serves as a frontline drug in tuberculosis treatment (1). Despite the fact that INH has been widely used as a first-line antitubercular agent (2, 3), its therapeutic value is usually accompanied by severe hepatotoxicity and lethal hepatic injury (4, 5). Although the pathophysiology of INH-induced liver injury might vary, the toxicity features of the drug, including hepatocellular steatosis, necrosis, and inflammatory infiltration, are nearly consistent (6, 7).Even though extensive studies expounding INH toxicity have been carried out, the exact mechanism of INH hepatotoxicity remains controversial. Among numerous established theories, an inflammatory stress theory has recently been widely used to explain the idiosyncrasy. One hypothesis is that inflammatory stress increases sensitivity to drug-induced liver injury (DILI) (8, 9). In this theory, an incidence of systemic inflammation might reduce the xenobiotic toxicity threshold, which could be easily accomplished by coadministration with an inflammatory agent (10), thus promoting drug toxicity. Lipopolysaccharide (LPS) is an outer cell wall membrane constituent of Gram-negative bacteria that has been comprehensively studied as an inflammatory agent with a major role in bacterial infections (11,12). Previous studies have suggested that LPS might intensify DILI (13-15), and, hence, a possible cornerstone role for LPS in INH-induced hepatotoxicity might be assumed.Oxidative stress, generated from the accumulation of reactive oxygen species (ROS), may be potentiated by different factors, including drugs and inflammation (16,17). In addition, oxidative stress plays a major role in several types of hepatic injury (18). Furthermore, with cytochrome P450 2E1 (CYP2E1) playing a major role in drug metabolism and the pathophysiology of DILI (19) and being considered a principal element in human susceptibility to chemical toxins (20), it plays a central part in oxidative stress, production of ROS, and hepatotoxic injury. Moreover, a previous report proposed that hepatic CYP2E1 plays a fundamental role in the propagation of INH-induced hepatotoxicity, mainly throughout ROS generation (21). Nevertheless, a full understanding of CYP2E1 as a major hepatotoxin-forming, catalyzing enzyme and its influence on INH-induced liver damage has not been completely achieved.Studies of the hepatotoxic mechanisms of INH were previously conducted using different animal models; however, results were accompanied by the absence of certain features of INH toxicity, i.e., delayed onset or inconsistency in severity compared to that in hu-

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“…FXR agonism increases BSEP, MRP2, and OST expression and represses NTCP and OATP expression in hepatocytes. CAR or PXR agonism increases OATP, SULT2A1, MRP2, MRP3, and MRP4 expression (Xie et al, 2001;Stahl et al, 2008;Halilbasic et al, 2013). The net effect of this NHR interplay, and its modulation by members of the BA pool, is increased efflux of BAs out of the hepatocyte, as well as shunting of BAs toward MRPs, especially after sulfation to 3-O-sulfates that are excreted in the urine (Van Berge Henegouwen et al, 1976;Keppler, 2011;Humbert et al, 2012).…”

Section: Mechanisms Leading To Drug-induced Cholestasis 569mentioning

confidence: 99%

Drug-Induced Perturbations of the Bile Acid Pool, Cholestasis, and Hepatotoxicity: Mechanistic Considerations beyond the Direct Inhibition of the Bile Salt Export Pump

et al. 2013

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The bile salt export pump (BSEP) is located on the canalicular plasma membrane of hepatocytes and plays an important role in the biliary clearance of bile acids (BAs). Therefore, any drug or new chemical entity that inhibits BSEP has the potential to cause cholestasis and possibly liver injury. In reality, however, one must consider the complexity of the BA pool, BA enterohepatic recirculation (EHR), extrahepatic (renal) BA clearance, and the interplay of multiple participant transporters and enzymes (e.g., sulfotransferase 2A1, multidrug resistance-associated protein 2, 3, and 4). Moreover, BAs undergo extensive enzyme-catalyzed amidation and are subjected to metabolism by enterobacteria during EHR. Expression of the various enzymes and transporters described above is governed by nuclear hormone receptors (NHRs) that mount an adaptive response when intracellular levels of BAs are increased. The intracellular trafficking of transporters, and their ability to mediate the vectorial transport of BAs, is governed by specific kinases also. Finally, bile flow, micelle formation, canalicular membrane integrity, and BA clearance can be influenced by the inhibition of multidrug resistant protein 3-or ATPase-aminophospholipid transporter-mediated phospholipid flux. Consequently, when screening compounds in a discovery setting or conducting mechanistic studies to address clinical findings, one has to consider the direct (inhibitory) effect of the parent drug and metabolites on multiple BA transporters, as well as inhibition of BA sulfation and amidation and NHR function. Vectorial BA transport, in addition to BA EHR and homoeostasis, could also be impacted by drug-dependent modulation of kinases and enterobacteria.

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Bile acid transporters and regulatory nuclear receptors in the liver and beyond

Cited by 320 publications

References 161 publications

Morphologic and Molecular Features of Hepatocellular Adenoma with Gadoxetic Acid–enhanced MR Imaging

Morphologic and Molecular Features of Hepatocellular Adenoma with Gadoxetic Acid–enhanced MR Imaging

Role of Inflammatory and Oxidative Stress, Cytochrome P450 2E1, and Bile Acid Disturbance in Rat Liver Injury Induced by Isoniazid and Lipopolysaccharide Cotreatment

Drug-Induced Perturbations of the Bile Acid Pool, Cholestasis, and Hepatotoxicity: Mechanistic Considerations beyond the Direct Inhibition of the Bile Salt Export Pump

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