The Experts below are selected from a list of 183 Experts worldwide ranked by ideXlab platform
Milan Jirsa - One of the best experts on this subject based on the ideXlab platform.
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The first Turkish family with Rotor Syndrome diagnosed at the molecular level.
Turk pediatri arsivi, 2020Co-Authors: Evren Gumus, Meryem Karaca, Uğur Deveci, Milan JirsaAbstract:Rotor Syndrome is defined as a self-limiting hyperbilirubinemia characterized by jaundice that does not need treatment, cause any morbidity or affect life expectancy. As far as the literature is evaluated, the number of patients with Rotor Syndrome diagnosed at the molecular level is less than 20 until today. In this case presentation, we aimed to present two siblings with Rotor Syndrome who were diagnosed at the molecular level. To the nest of our knowledge, these patients are the first Turkish patients with Rotor Syndrome diagnosed at the molecular level.
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Radionuclide cholescintigraphy in genetically confirmed Rotor Syndrome
Pediatrics international : official journal of the Japan Pediatric Society, 2015Co-Authors: Pavel Sirucek, Milan Jirsa, Astrida Sulakova, Lubomir Mrhac, Martin Havel, Otakar KraftAbstract:A 7-year-old girl had been followed up for persistent conjugated hyperbilirubinemia since birth. Alanine aminotransferase, aspartate aminotransferase and γ-glutamyl transpeptidase activity was within the normal range, and liver protein synthesis had always been normal. Infectious etiology of jaundice, autoimmune diseases, drug-induced liver injury, hemolytic anemia, α-1 anti-trypsin deficiency, Wilson disease and Gilbert Syndrome were ruled out. At the age of 8 years the patient underwent radionuclide dynamic cholescintigraphy, indicating poor accumulation of the radiotracer in the liver on one hand, and severe retention of the radiopharmaceutical in the blood pool (including the heart) on the other hand. Rotor Syndrome was suspected and finally confirmed on molecular analysis. This case represents the first cholescintigraphy report in a pediatric patient with genetically proven Rotor Syndrome.
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Down-regulation of OATP1B proteins correlates with hyperbilirubinemia in advanced cholestasis
International journal of clinical and experimental pathology, 2015Co-Authors: Eva Sticova, Alena Lodererova, E. Van De Steeg, Sona Frankova, Marek Kollar, Věra Lánská, Radana Kotalova, Tomas Dedic, Alfred H. Schinkel, Milan JirsaAbstract:Aim: Organic anion-transporting polypeptides OATP1B1 and OATP1B3 are sinusoidal membrane transporters mediating liver uptake of a wide range of substrates including conjugated and unconjugated bilirubin, xenobiotics and drugs. Absence of OATP1Bs in the liver causes Rotor Syndrome. Our aim was to correlate OATP1B expression with hyperbilirubinemia in common liver diseases. Methods: Immunoreactivity of five antibodies against human OATP1Bs was tested on frozen and formalin-fixed paraffin-embedded liver tissue of mouse strains transgenic for SLCO1B1 or SLCO1B3 and on human specimens. The proportion of hepatocytes expressing OATP1Bs was then assessed immunohistologically in formalin-fixed paraffin-embedded liver samples obtained from patients with hepatocellular and primary biliary liver diseases. UGT1A1 promoter TATA-box and SLCO1B1 rs4149056 genotyping was performed to rule out individuals predisposed to hyperbilirubinemia. Results: The most specific detection of OATP1B3 was achieved with the H-52 (sc-98981) antibody. OATP1B1 was specifically recognized with the ESL (ab15441) anti-OATP1B1 antibody, but only in frozen sections. The MDQ (ab15442) anti-OATP1B1 antibody cross-reacted with both OATP1B proteins in liver tissue of the transgenic mouse strains. Expression of the OATP1B proteins was decreased in advanced liver diseases and inversely correlated with serum bilirubin levels. The reduction was more pronounced in advanced primary biliary diseases (1.9±1.1 vs. 2.7±0.6; P=0.009). Conclusions: Down-regulation of OATP1B proteins may contribute to pathogenesis of jaundice accompanying advanced cholestatic liver diseases.
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Original Article Down-regulation of OATP1B proteins correlates with hyperbilirubinemia in advanced cholestasis
2015Co-Authors: Eva Sticova, Evita Van De Steeg, Alena Lodererova, Sona Frankova, Marek Kollar, Věra Lánská, Radana Kotalova, Tomas Dedic, Alfred H. Schinkel, Milan JirsaAbstract:Aim: Organic anion-transporting polypeptides OATP1B1 and OATP1B3 are sinusoidal membrane trans- porters mediating liver uptake of a wide range of substrates including conjugated and unconjugated bilirubin, xe- nobiotics and drugs. Absence of OATP1Bs in the liver causes Rotor Syndrome. Our aim was to correlate OATP1B expression with hyperbilirubinemia in common liver diseases. Methods: Immunoreactivity of five antibodies against human OATP1Bs was tested on frozen and formalin-fixed paraffin-embedded liver tissue of mouse strains trans - genic for SLCO1B1 or SLCO1B3 and on human specimens. The proportion of hepatocytes expressing OATP1Bs was then assessed immunohistologically in formalin-fixed paraffin-embedded liver samples obtained from patients with hepatocellular and primary biliary liver diseases. UGT1A1 promoter TATA-box and SLCO1B1 rs4149056 genotyp- ing was performed to rule out individuals predisposed to hyperbilirubinemia. Results: The most specific detection of OATP1B3 was achieved with the H-52 (sc-98981) antibody. OATP1B1 was specifically recognized with the ESL (ab15441) anti-OATP1B1 antibody, but only in frozen sections. The MDQ (ab15442) anti-OATP1B1 antibody cross- reacted with both OATP1B proteins in liver tissue of the transgenic mouse strains. Expression of the OATP1B pro- teins was decreased in advanced liver diseases and inversely correlated with serum bilirubin levels. The reduction was more pronounced in advanced primary biliary diseases (1.9±1.1 vs. 2.7±0.6; P=0.009). Conclusions: Down- regulation of OATP1B proteins may contribute to pathogenesis of jaundice accompanying advanced cholestatic liver diseases.
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New insights in bilirubin metabolism and their clinical implications.
World journal of gastroenterology, 2013Co-Authors: Eva Sticova, Milan JirsaAbstract:Bilirubin, a major end product of heme breakdown, is an important constituent of bile, responsible for its characteristic colour. Over recent decades, our understanding of bilirubin metabolism has expanded along with the processes of elimination of other endogenous and exogenous anionic substrates, mediated by the action of multiple transport systems at the sinusoidal and canalicular membrane of hepatocytes. Several inherited disorders characterised by impaired bilirubin conjugation (Crigler-Najjar Syndrome type I and type II, Gilbert Syndrome) or transport (Dubin-Johnson and Rotor Syndrome) result in various degrees of hyperbilirubinemia of either the predominantly unconjugated or predominantly conjugated type. Moreover, disrupted regulation of hepatobiliary transport systems can explain jaundice in many acquired liver disorders. In this review, we discuss the recent data on liver bilirubin handling based on the discovery of the molecular basis of Rotor Syndrome. The data show that a substantial fraction of bilirubin conjugates is primarily secreted by MRP3 at the sinusoidal membrane into the blood, from where they are subsequently reuptaken by sinusoidal membrane-bound organic anion transporting polypeptides OATP1B1 and OATP1B3. OATP1B proteins are also responsible for liver clearance of bilirubin conjugated in splanchnic organs, such as the intestine and kidney, and for a number of endogenous compounds, xenobiotics and drugs. Absence of one or both OATP1B proteins thus may have serious impact on toxicity of commonly used drugs cleared by this system such as statins, sartans, methotrexate or rifampicin. The liver-blood cycling of conjugated bilirubin is impaired in cholestatic and parenchymal liver diseases and this impairment most likely contributes to jaundice accompanying these disorders.
Eva Sticova - One of the best experts on this subject based on the ideXlab platform.
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Down-regulation of OATP1B proteins correlates with hyperbilirubinemia in advanced cholestasis
International journal of clinical and experimental pathology, 2015Co-Authors: Eva Sticova, Alena Lodererova, E. Van De Steeg, Sona Frankova, Marek Kollar, Věra Lánská, Radana Kotalova, Tomas Dedic, Alfred H. Schinkel, Milan JirsaAbstract:Aim: Organic anion-transporting polypeptides OATP1B1 and OATP1B3 are sinusoidal membrane transporters mediating liver uptake of a wide range of substrates including conjugated and unconjugated bilirubin, xenobiotics and drugs. Absence of OATP1Bs in the liver causes Rotor Syndrome. Our aim was to correlate OATP1B expression with hyperbilirubinemia in common liver diseases. Methods: Immunoreactivity of five antibodies against human OATP1Bs was tested on frozen and formalin-fixed paraffin-embedded liver tissue of mouse strains transgenic for SLCO1B1 or SLCO1B3 and on human specimens. The proportion of hepatocytes expressing OATP1Bs was then assessed immunohistologically in formalin-fixed paraffin-embedded liver samples obtained from patients with hepatocellular and primary biliary liver diseases. UGT1A1 promoter TATA-box and SLCO1B1 rs4149056 genotyping was performed to rule out individuals predisposed to hyperbilirubinemia. Results: The most specific detection of OATP1B3 was achieved with the H-52 (sc-98981) antibody. OATP1B1 was specifically recognized with the ESL (ab15441) anti-OATP1B1 antibody, but only in frozen sections. The MDQ (ab15442) anti-OATP1B1 antibody cross-reacted with both OATP1B proteins in liver tissue of the transgenic mouse strains. Expression of the OATP1B proteins was decreased in advanced liver diseases and inversely correlated with serum bilirubin levels. The reduction was more pronounced in advanced primary biliary diseases (1.9±1.1 vs. 2.7±0.6; P=0.009). Conclusions: Down-regulation of OATP1B proteins may contribute to pathogenesis of jaundice accompanying advanced cholestatic liver diseases.
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Original Article Down-regulation of OATP1B proteins correlates with hyperbilirubinemia in advanced cholestasis
2015Co-Authors: Eva Sticova, Evita Van De Steeg, Alena Lodererova, Sona Frankova, Marek Kollar, Věra Lánská, Radana Kotalova, Tomas Dedic, Alfred H. Schinkel, Milan JirsaAbstract:Aim: Organic anion-transporting polypeptides OATP1B1 and OATP1B3 are sinusoidal membrane trans- porters mediating liver uptake of a wide range of substrates including conjugated and unconjugated bilirubin, xe- nobiotics and drugs. Absence of OATP1Bs in the liver causes Rotor Syndrome. Our aim was to correlate OATP1B expression with hyperbilirubinemia in common liver diseases. Methods: Immunoreactivity of five antibodies against human OATP1Bs was tested on frozen and formalin-fixed paraffin-embedded liver tissue of mouse strains trans - genic for SLCO1B1 or SLCO1B3 and on human specimens. The proportion of hepatocytes expressing OATP1Bs was then assessed immunohistologically in formalin-fixed paraffin-embedded liver samples obtained from patients with hepatocellular and primary biliary liver diseases. UGT1A1 promoter TATA-box and SLCO1B1 rs4149056 genotyp- ing was performed to rule out individuals predisposed to hyperbilirubinemia. Results: The most specific detection of OATP1B3 was achieved with the H-52 (sc-98981) antibody. OATP1B1 was specifically recognized with the ESL (ab15441) anti-OATP1B1 antibody, but only in frozen sections. The MDQ (ab15442) anti-OATP1B1 antibody cross- reacted with both OATP1B proteins in liver tissue of the transgenic mouse strains. Expression of the OATP1B pro- teins was decreased in advanced liver diseases and inversely correlated with serum bilirubin levels. The reduction was more pronounced in advanced primary biliary diseases (1.9±1.1 vs. 2.7±0.6; P=0.009). Conclusions: Down- regulation of OATP1B proteins may contribute to pathogenesis of jaundice accompanying advanced cholestatic liver diseases.
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New insights in bilirubin metabolism and their clinical implications.
World journal of gastroenterology, 2013Co-Authors: Eva Sticova, Milan JirsaAbstract:Bilirubin, a major end product of heme breakdown, is an important constituent of bile, responsible for its characteristic colour. Over recent decades, our understanding of bilirubin metabolism has expanded along with the processes of elimination of other endogenous and exogenous anionic substrates, mediated by the action of multiple transport systems at the sinusoidal and canalicular membrane of hepatocytes. Several inherited disorders characterised by impaired bilirubin conjugation (Crigler-Najjar Syndrome type I and type II, Gilbert Syndrome) or transport (Dubin-Johnson and Rotor Syndrome) result in various degrees of hyperbilirubinemia of either the predominantly unconjugated or predominantly conjugated type. Moreover, disrupted regulation of hepatobiliary transport systems can explain jaundice in many acquired liver disorders. In this review, we discuss the recent data on liver bilirubin handling based on the discovery of the molecular basis of Rotor Syndrome. The data show that a substantial fraction of bilirubin conjugates is primarily secreted by MRP3 at the sinusoidal membrane into the blood, from where they are subsequently reuptaken by sinusoidal membrane-bound organic anion transporting polypeptides OATP1B1 and OATP1B3. OATP1B proteins are also responsible for liver clearance of bilirubin conjugated in splanchnic organs, such as the intestine and kidney, and for a number of endogenous compounds, xenobiotics and drugs. Absence of one or both OATP1B proteins thus may have serious impact on toxicity of commonly used drugs cleared by this system such as statins, sartans, methotrexate or rifampicin. The liver-blood cycling of conjugated bilirubin is impaired in cholestatic and parenchymal liver diseases and this impairment most likely contributes to jaundice accompanying these disorders.
Piter J. Bosma - One of the best experts on this subject based on the ideXlab platform.
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ATP11C targets basolateral bile salt transporter proteins in mouse central hepatocytes.
Hepatology (Baltimore Md.), 2016Co-Authors: Dirk R. De Waart, Jyoti Naik, Karina S. Utsunomiya, Suzanne Duijst, Kam S. Ho-mok, Ruth Bolier, Johan K. Hiralall, Laura N. Bull, Piter J. Bosma, Ronald P.j. Oude ElferinkAbstract:UNLABELLED ATP11C is a homolog of ATP8B1, both of which catalyze the transport of phospholipids in biological membranes. Mutations in ATP8B1 cause progressive familial intrahepatic cholestasis type1 in humans, which is characterized by a canalicular cholestasis. Mice deficient in ATP11C are characterized by a conjugated hyperbilirubinemia and an unconjugated hypercholanemia. Here, we have studied the hypothesis that ATP11C deficiency interferes with basolateral uptake of unconjugated bile salts, a process mediated by organic anion-transporting polypeptide (OATP) 1B2. ATP11C localized to the basolateral membrane of central hepatocytes in the liver lobule of control mice. In ATP11C-deficient mice, plasma total bilirubin levels were 6-fold increased, compared to control, of which ∼65% was conjugated and ∼35% unconjugated. Plasma total bile salts were 10-fold increased and were mostly present as unconjugated species. Functional studies in ATP11C-deficient mice indicated that hepatic uptake of unconjugated bile salts was strongly impaired whereas uptake of conjugated bile salts was unaffected. Western blotting and immunofluorescence analysis demonstrated near absence of basolateral bile salt uptake transporters OATP1B2, OATP1A1, OATP1A4, and Na(+) -taurocholate-cotransporting polypeptide only in central hepatocytes of ATP11C-deficient liver. In vivo application of the proteasome inhibitor, bortezomib, partially restored expression of these proteins, but not their localization. Furthermore, we observed post-translational down-regulation of ATP11C protein in livers from cholestatic mice, which coincided with reduced OATP1B2 levels. CONCLUSIONS ATP11C is essential for basolateral membrane localization of multiple bile salt transport proteins in central hepatocytes and may act as a gatekeeper to prevent hepatic bile salt overload. Conjugated hyperbilirubinemia and unconjugated hypercholanemia and loss of OATP expression in ATP11C-deficient liver strongly resemble the characteristics of Rotor Syndrome, suggesting that mutations in ATP11C can predispose to Rotor Syndrome. (Hepatology 2016;64:161-174).
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Gene Replacement Therapy for Genetic Hepatocellular Jaundice
Clinical Reviews in Allergy & Immunology, 2015Co-Authors: Remco Dijk, Ulrich Beuers, Piter J. BosmaAbstract:Jaundice results from the systemic accumulation of bilirubin, the final product of the catabolism of haem. Inherited liver disorders of bilirubin metabolism and transport can result in reduced hepatic uptake, conjugation or biliary secretion of bilirubin. In patients with Rotor Syndrome, bilirubin (re)uptake is impaired due to the deficiency of two basolateral/sinusoidal hepatocellular membrane proteins, organic anion-transporting polypeptide 1B1 (OATP1B1) and OATP1B3. Dubin-Johnson Syndrome is caused by a defect in the ATP-dependent canalicular transporter, multidrug resistance-associated protein 2 (MRP2), which mediates the export of conjugated bilirubin into bile. Both disorders are benign and not progressive and are characterised by elevated serum levels of mainly conjugated bilirubin. Uridine diphospho-glucuronosyl transferase 1A1 (UGT1A1) is responsible for the glucuronidation of bilirubin; deficiency of this enzyme results in unconjugated hyperbilirubinaemia. Gilbert Syndrome is the mild and benign form of inherited unconjugated hyperbilirubinaemia and is mostly caused by reduced promoter activity of the UGT1A1 gene. Crigler-Najjar Syndrome is the severe inherited form of unconjugated hyperbilirubinaemia due to mutations in the UGT1A1 gene, which can cause kernicterus early in life and can be even lethal when left untreated. Due to major disadvantages of the current standard treatments for Crigler-Najjar Syndrome, phototherapy and liver transplantation, new effective therapeutic strategies are under development. Here, we review the clinical features, pathophysiology and genetic background of these inherited disorders of bilirubin metabolism and transport. We also discuss the upcoming treatment option of viral gene therapy for genetic disorders such as Crigler-Najjar Syndrome and the possible immunological consequences of this therapy.
Daniel Dhumeaux - One of the best experts on this subject based on the ideXlab platform.
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Inherited Disorders of Bilirubin Transport and Conjugation: New Insights Into Molecular Mechanisms and Consequences
Gastroenterology, 2014Co-Authors: S Erlinger, Irwin M. Arias, Daniel DhumeauxAbstract:Inherited disorders of bilirubin metabolism might reduce bilirubin uptake by hepatocytes, bilirubin conjugation, or secretion of bilirubin into bile. Reductions in uptake could increase levels of unconjugated or conjugated bilirubin (Rotor Syndrome). Defects in bilirubin conjugation could increase levels of unconjugated bilirubin; the effects can be benign and frequent (Gilbert Syndrome) or rare but severe, increasing the risk of bilirubin encephalopathy (Crigler–Najjar Syndrome). Impairment of bilirubin secretion leads to accumulation of conjugated bilirubin (Dubin–Johnson Syndrome). We review the genetic causes and pathophysiology of disorders of bilirubin transport and conjugation as well as clinical and therapeutic aspects. We also discuss the possible mechanisms by which hyperbilirubinemia protects against cardiovascular disease and the metabolic Syndrome and the effects of specific genetic variants on drug metabolism and cancer development.
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Hereditary conjugated hyperbilirubinaemia: 37 years later
Journal of hepatology, 2012Co-Authors: Daniel Dhumeaux, S ErlingerAbstract:Bilirubin, a breakdown product of heme, is normally glucuronidated and excreted by the liver into bile. Failure of this system can lead to a buildup of conjugated bilirubin in the blood, resulting in jaundice. The mechanistic basis of bilirubin excretion and hyperbilirubinemia Syndromes is largely understood, but that of Rotor Syndrome, an autosomal recessive disorder characterized by conjugated hyperbilirubinemia, coproporphyrinuria, and near-absent hepatic uptake of anionic diagnostics, has remained enigmatic. Here, we analyzed 8 Rotor-Syndrome families and found that Rotor Syndrome was linked to mutations predicted to cause complete and simultaneous deficiencies of the organic anion transporting polypeptides OATP1B1 and OATP1B3. These important detoxification-limiting proteins mediate uptake and clearance of countless drugs and drug conjugates across the sinusoidal hepatocyte membrane. OATP1B1 polymorphisms have previously been linked to drug hypersensitivities. Using mice deficient in Oatp1a/1b and in the multispecific sinusoidal export pump Abcc3, we found that Abcc3 secretes bilirubin conjugates into the blood, while Oatp1a/1b transporters mediate their hepatic re uptake. Transgenic expression of human OATP1B1 or OATP1B3 restored the function of this detoxification-enhancing liver-blood shuttle in Oatp1a/1b-deficient mice. Within liver lobules, this shuttle may allow flexible transfer of bilirubin conjugates (and probably also drug conjugates) formed in upstream hepatocytes to downstream hepatocytes, thereby preventing local saturation of further detoxification processes and hepatocyte toxic injury. Thus, disruption of hepatic reuptake of bilirubin glucuronide due to coexisting OATP1B1 and OATP1B3 deficiencies explains Rotor-type hyperbilirubinemia.Moreover, OATP1B1 and OATP1B3 null mutations may confer substantial drug toxicity risks.
S Erlinger - One of the best experts on this subject based on the ideXlab platform.
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Inherited Disorders of Bilirubin Transport and Conjugation: New Insights Into Molecular Mechanisms and Consequences
Gastroenterology, 2014Co-Authors: S Erlinger, Irwin M. Arias, Daniel DhumeauxAbstract:Inherited disorders of bilirubin metabolism might reduce bilirubin uptake by hepatocytes, bilirubin conjugation, or secretion of bilirubin into bile. Reductions in uptake could increase levels of unconjugated or conjugated bilirubin (Rotor Syndrome). Defects in bilirubin conjugation could increase levels of unconjugated bilirubin; the effects can be benign and frequent (Gilbert Syndrome) or rare but severe, increasing the risk of bilirubin encephalopathy (Crigler–Najjar Syndrome). Impairment of bilirubin secretion leads to accumulation of conjugated bilirubin (Dubin–Johnson Syndrome). We review the genetic causes and pathophysiology of disorders of bilirubin transport and conjugation as well as clinical and therapeutic aspects. We also discuss the possible mechanisms by which hyperbilirubinemia protects against cardiovascular disease and the metabolic Syndrome and the effects of specific genetic variants on drug metabolism and cancer development.
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Hereditary conjugated hyperbilirubinaemia: 37 years later
Journal of hepatology, 2012Co-Authors: Daniel Dhumeaux, S ErlingerAbstract:Bilirubin, a breakdown product of heme, is normally glucuronidated and excreted by the liver into bile. Failure of this system can lead to a buildup of conjugated bilirubin in the blood, resulting in jaundice. The mechanistic basis of bilirubin excretion and hyperbilirubinemia Syndromes is largely understood, but that of Rotor Syndrome, an autosomal recessive disorder characterized by conjugated hyperbilirubinemia, coproporphyrinuria, and near-absent hepatic uptake of anionic diagnostics, has remained enigmatic. Here, we analyzed 8 Rotor-Syndrome families and found that Rotor Syndrome was linked to mutations predicted to cause complete and simultaneous deficiencies of the organic anion transporting polypeptides OATP1B1 and OATP1B3. These important detoxification-limiting proteins mediate uptake and clearance of countless drugs and drug conjugates across the sinusoidal hepatocyte membrane. OATP1B1 polymorphisms have previously been linked to drug hypersensitivities. Using mice deficient in Oatp1a/1b and in the multispecific sinusoidal export pump Abcc3, we found that Abcc3 secretes bilirubin conjugates into the blood, while Oatp1a/1b transporters mediate their hepatic re uptake. Transgenic expression of human OATP1B1 or OATP1B3 restored the function of this detoxification-enhancing liver-blood shuttle in Oatp1a/1b-deficient mice. Within liver lobules, this shuttle may allow flexible transfer of bilirubin conjugates (and probably also drug conjugates) formed in upstream hepatocytes to downstream hepatocytes, thereby preventing local saturation of further detoxification processes and hepatocyte toxic injury. Thus, disruption of hepatic reuptake of bilirubin glucuronide due to coexisting OATP1B1 and OATP1B3 deficiencies explains Rotor-type hyperbilirubinemia.Moreover, OATP1B1 and OATP1B3 null mutations may confer substantial drug toxicity risks.
