99mTc-HIDA cholescintigraphy in Dubin-Johnson and Rotor syndromes.

Bar‐Meir, Simon; Baron, Jan; Seligson, U; Gottesfeld, F.; Levy, Rebecca; Gilat, T

doi:10.1148/radiology.142.3.7063695

Cited by 46 publications

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“…This correlated with long-standing observations in Dubin-Johnson syndrome of abnormal handling of 99m Tc-mebrofenin analogs with hepatic accumulation and inability to clear radiotracers over time (20). These findings established that 99m Tc-mebrofenin imaging will provide a specific diagnostic test for Dubin-Johnson syndrome and for other disorders characterized by the loss of Abcc2 activity.…”

Section: Discussionsupporting

confidence: 79%

Adenosine Triphosphate–Binding Cassette Subfamily C Member 2 Is the Major Transporter of the Hepatobiliary Imaging Agent ^99mTc-Mebrofenin

Bhargava¹,

Joseph²,

Ananthanarayanan³

et al. 2009

J Nucl Med

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The organic anion 99m Tc-N-[2- [(3-bromo-2,4,6-trimethylphenyl)amino]-2-oxoethyl]-N-(carboxymethyl)-glycine ( 99m Tc-mebrofenin) and its analogs are widely used for hepatobiliary imaging. Identification of the mechanisms directing bile canalicular transport of these agents will provide insights into the basis of their hepatic handling for assessing perturbations. Methods: We performed studies in animals, including healthy Fischer 344 rats or rats treated with carbon tetrachloride or intrasplenic cell transplantation and healthy Wistar rats or HsdAMC:TR-Abcc2 mutant rats in Wistar background. Onset of hepatic inflammation was verified by analysis of carbon uptake in Kupffer cells. Hepatic clearance of 99m Tc-mebrofenin was studied with dynamic imaging, and fractional retention of peak hepatic mebrofenin activity after 60 min was determined. Changes in the expression of bile canalicular transporters were analyzed by real-time polymerase chain reaction and Western blots. Results: Carbon tetrachloride and cell transplantation produced hepatic inflammation with activation of Kupffer cells, resulting in a rapid decline in the expression of the bile canalicular transporters Abcb4, Abcb11, and Abcc2. Among these transporters, decreased expression of Abcc2 was most prominent, and this decline persisted for 4 wk. Next, we examined 99m Tc-mebrofenin excretion in HsdAMC:TR-Abcc2 mutant rats (in which Abcc2 expression is naturally inactivated), compared with their healthy counterparts. In healthy HsdRccHan:WIST rats, only 23% 6 3% of the peak 99m Tc-mebrofenin activity was retained after 60 min. By contrast, in HsdAMC:TR-Abcc2 mutant rats, 73% 6 5% of the peak 99m Tc-mebrofenin activity was retained (P , 0.001). Moreover, the administration of cyclosporin A markedly inhibited 99m Tc-mebrofenin excretion in healthy rats, with no further effect on already impaired 99m Tc-mebrofenin excretion in HsdAMC:TR-Abcc2 mutant rats. Hepatic excretion of 99m Tc-mebrofenin was largely dependent on Abcc2. This molecular basis of 99m Tc-mebrofenin excretion will advance studies of pathophysiologic mechanisms in hepatic Abcc2 pathways.

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Section: Discussionsupporting

confidence: 79%

Adenosine Triphosphate–Binding Cassette Subfamily C Member 2 Is the Major Transporter of the Hepatobiliary Imaging Agent ^99mTc-Mebrofenin

Bhargava¹,

Joseph²,

Ananthanarayanan³

et al. 2009

J Nucl Med

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“…Presence of at least one wild-type (functional) allele of either SLCO1B1 or SLCO1B3 prevents Rotor-type hyperbilirubinemia (Jirsa et al, 2012;van de Steeg et al, 2012). Remarkably, these patients are characterized by predominantly conjugated hyperbilirubinemia, associated with delayed elimination from blood of several anionic diagnostic dyes and with impaired uptake into hepatocytes (Wolpert et al, 1977;Bar-Meir et al, 1982;Jirsa et al, 2012). The exact source of this conjugated plasma bilirubin in patients with Rotor syndrome and in the knockout mice lacking Oatp1a/1b uptake transporters has not been fully clarified (van de Steeg et al, 2012).…”

Section: Predominantly Conjugated Hyperbilirubinemia In Rotor Syndromementioning

confidence: 99%

The Roles of MRP2, MRP3, OATP1B1, and OATP1B3 in Conjugated Hyperbilirubinemia

2014

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Increased concentrations of bilirubin glucuronides in blood plasma indicate hepatocellular dysfunction. Elucidation of the transport processes of bilirubin conjugates across the basolateral (sinusoidal) and the canalicular plasma membrane domains of hepatocytes has decisively contributed to our current understanding of the molecular basis of conjugated hyperbilirubinemia in human liver diseases. Under normal conditions, unconjugated bilirubin is taken up into hepatocytes by transporters of the organic anion-transporting polypeptide (OATP) family, followed by conjugation with glucuronic acid, and ATP-dependent transport into bile. This efflux across the canalicular membrane is mediated by multidrug resistance protein 2 (MRP2 or ABCC2), which is a 190-kDa glycoprotein transporting with high affinity and efficiency monoglucuronosyl bilirubin and bisglucuronosyl bilirubin into bile. MRP2 is hereditarily deficient in human Dubin-Johnson syndrome. Under pathophysiological conditions such as cholestatic liver injury and MRP2 inhibition, the basolateral efflux pump multidrug resistance protein 3 (MRP3 or ABCC3) is responsible for the occurrence of conjugated hyperbilirubinemia. MRP3 is a glycoprotein with a similar molecular mass as MRP2, with 48% amino acid identity, and with overlapping substrate specificity. Human MRP3 is the only basolateral efflux pump shown to transport bilirubin glucuronides. In human and rat hepatocytes, MRP3/Mrp3 is strongly upregulated under conditions of cholestasis and MRP2 deficiency. This is in line with the concept that basolateral efflux pumps of the hepatocyte compensate for impaired canalicular efflux of compounds into bile and contribute to balance the rate of uptake or synthesis of compounds in hepatocytes with the capacity for efflux into bile.

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“…Rotor syndrome (RS; OMIM %237450) is a rare, benign hereditary conjugated hyperbilirubinemia, also featuring coproporphyrinuria and strongly reduced liver uptake of many diagnostic compounds, including cholescintigraphic tracers (1)(2)(3)(4)(5)(6). RS is an autosomal recessive disorder that clinically resembles another conjugated hyperbilirubinemia, the Dubin-Johnson syndrome (DJS; OMIM #237500) (7,8).…”

Section: Introductionmentioning

confidence: 99%

Complete OATP1B1 and OATP1B3 deficiency causes human Rotor syndrome by interrupting conjugated bilirubin reuptake into the liver

Stránecký²,

et al. 2012

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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 Rotorsyndrome 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 reuptake. 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.

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99mTc-HIDA cholescintigraphy in Dubin-Johnson and Rotor syndromes.

Cited by 46 publications

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Adenosine Triphosphate–Binding Cassette Subfamily C Member 2 Is the Major Transporter of the Hepatobiliary Imaging Agent ^99mTc-Mebrofenin

Adenosine Triphosphate–Binding Cassette Subfamily C Member 2 Is the Major Transporter of the Hepatobiliary Imaging Agent ^99mTc-Mebrofenin

The Roles of MRP2, MRP3, OATP1B1, and OATP1B3 in Conjugated Hyperbilirubinemia

Complete OATP1B1 and OATP1B3 deficiency causes human Rotor syndrome by interrupting conjugated bilirubin reuptake into the liver

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99mTc-HIDA cholescintigraphy in Dubin-Johnson and Rotor syndromes.

Cited by 46 publications

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Adenosine Triphosphate–Binding Cassette Subfamily C Member 2 Is the Major Transporter of the Hepatobiliary Imaging Agent 99mTc-Mebrofenin

Adenosine Triphosphate–Binding Cassette Subfamily C Member 2 Is the Major Transporter of the Hepatobiliary Imaging Agent 99mTc-Mebrofenin

The Roles of MRP2, MRP3, OATP1B1, and OATP1B3 in Conjugated Hyperbilirubinemia

Complete OATP1B1 and OATP1B3 deficiency causes human Rotor syndrome by interrupting conjugated bilirubin reuptake into the liver

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Adenosine Triphosphate–Binding Cassette Subfamily C Member 2 Is the Major Transporter of the Hepatobiliary Imaging Agent ^99mTc-Mebrofenin

Adenosine Triphosphate–Binding Cassette Subfamily C Member 2 Is the Major Transporter of the Hepatobiliary Imaging Agent ^99mTc-Mebrofenin