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Statements

Subject Item
n2:RIV%2F00023001%3A_____%2F12%3A00056322%21RIV13-MZ0-00023001
rdf:type
n11:Vysledek skos:Concept
rdfs:seeAlso
http://www.jci.org/articles/view/59526/pdf
dcterms:description
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 Oatp 1a/1b and in the multispecific sinusoidal export pump Abcc3, we found that Abcc3 secretes bilirubin conjugates into the blood, while Oatp 1a/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. 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 Oatp 1a/1b and in the multispecific sinusoidal export pump Abcc3, we found that Abcc3 secretes bilirubin conjugates into the blood, while Oatp 1a/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.
dcterms:title
Complete OATP1B1 and OATP1B3 deficiency causes human Rotor syndrome by interrupting conjugated bilirubin reuptake into the liver Complete OATP1B1 and OATP1B3 deficiency causes human Rotor syndrome by interrupting conjugated bilirubin reuptake into the liver
skos:prefLabel
Complete OATP1B1 and OATP1B3 deficiency causes human Rotor syndrome by interrupting conjugated bilirubin reuptake into the liver Complete OATP1B1 and OATP1B3 deficiency causes human Rotor syndrome by interrupting conjugated bilirubin reuptake into the liver
skos:notation
RIV/00023001:_____/12:00056322!RIV13-MZ0-00023001
n11:predkladatel
n12:ico%3A00023001
n3:aktivita
n16:Z n16:P n16:I
n3:aktivity
I, P(1M0520), Z(MSM0021620806), Z(MZ0IKEM2005)
n3:cisloPeriodika
2
n3:dodaniDat
n14:2013
n3:domaciTvurceVysledku
n9:7545622 n9:7088434
n3:druhVysledku
n18:J
n3:duvernostUdaju
n7:S
n3:entitaPredkladatele
n10:predkladatel
n3:idSjednocenehoVysledku
128161
n3:idVysledku
RIV/00023001:_____/12:00056322
n3:jazykVysledku
n20:eng
n3:klicovaSlova
Multidrug-resistance; Dubin-Johanson syndrome; Basolateral hepatocyte membrane; Anion-transporting polypeptides
n3:klicoveSlovo
n17:Basolateral%20hepatocyte%20membrane n17:Anion-transporting%20polypeptides n17:Multidrug-resistance n17:Dubin-Johanson%20syndrome
n3:kodStatuVydavatele
US - Spojené státy americké
n3:kontrolniKodProRIV
[CADBF804C2D5]
n3:nazevZdroje
Journal of Clinical Investigation
n3:obor
n19:FA
n3:pocetDomacichTvurcuVysledku
2
n3:pocetTvurcuVysledku
16
n3:projekt
n4:1M0520
n3:rokUplatneniVysledku
n14:2012
n3:svazekPeriodika
122
n3:tvurceVysledku
Kenworthy, Kathryn E Elferink, Ronald PJ Oude Stranecky, Viktor al-Edreesi, Mahammad Wagenaar, Els Schinkel, Alfred H van Esch, Anita van de Steeg, Evita Jirsa, Milan Knisely, AS Noskova, Lenka de Waart, Dirk R Hartmannova, Hana Kmoch, Stanislav Sticová, Eva Hrebicek, Martin
n3:wos
000299765800018
n3:zamer
n6:MSM0021620806 n6:MZ0IKEM2005
s:issn
0021-9738
s:numberOfPages
10
n21:doi
10.1172/JCI59526