title: Targeted pharmacotherapy in progressive familial intrahepatic cholestasis type 2: Evidence for improvement of cholestasis with 4-phenylbutyrate.
abstract: Progressive familial intrahepatic cholestasis type 2 (PFIC2) is a result of mutations in ABCB11 encoding bile salt export pump (BSEP), the canalicular bile salt export pump of hepatocyte. In some PFIC2 patients with missense mutations, BSEP is not detected at the canaliculus owing to mistrafficking of BSEP mutants. In vitro, chaperone drugs, such as 4-phenylbutyrate (4-PB), have been shown to partially correct mistrafficking. Four PFIC2 patients harboring at least one missense mutation (p.G982R, p.R1128C, and p.T1210P) were treated orally with 4-PB and followed prospectively. Patient mutations were reproduced in a Bsep/green fluorescent protein plasmid. Cellular localization of the resulting Bsep mutants was studied in a hepatocellular line (Can 10), and effects of treatment with 4-PB and/or ursodeoxycholic acid (UDCA) were assessed. In Can 10 cells, Bsep mutants were detected in the endoplasmic reticulum instead of at the canalicular membrane. Treatment with 4-PB and UDCA partially corrected Bsep mutant targeting. With 4-PB, we observed, in all patients, a decrease of pruritus and serum bile acid concentration (BAC) as well as an improvement of serum liver tests. Pathological liver injuries improved, and BSEP, which was not detected at the canalicular membrane before treatment, appeared at the canalicular membrane. Bile analyses showed an increase in BAC with 4-PB. Patient conditions remained stable with a median follow-up of 40 months (range, 3-53), and treatment tolerance was good.
  
  
  CONCLUSIONS
  4-PB therapy may be efficient in selected patients with PFIC2 owing to ABCB11 missense mutations affecting BSEP canalicular targeting. Bile secretion improvement may be a result of the ability of 4-PB to retarget mutated BSEP.
authors.affiliation: Pediatric hepatology and pediatric liver transplantation unit and National Reference Centre for rare pediatric liver diseases, Bicêtre Universitary Hospital, Faculty of Medicine Paris-Sud, University of Paris-Sud 11, Assistance Publique-Hôpitaux de Paris, Le Kremlin Bicêtre, Paris, France.|INSERM, UMR-S1174, Hepatinov, University of Paris-Sud 11, Orsay, France.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Gonzales
authors.affiliation: INSERM, UMR-S1174, Hepatinov, University of Paris-Sud 11, Orsay, France.
authors.forename: Brigitte
authors.initials: B
authors.lastname: Grosse
authors.affiliation: INSERM, UMR-S1174, Hepatinov, University of Paris-Sud 11, Orsay, France.
authors.forename: Brice
authors.initials: B
authors.lastname: Schuller
authors.affiliation: Biochemistry, Bicêtre Universitary Hospital, Faculty of Medicine Paris-Sud, University of Paris-Sud 11, Assistance Publique-Hôpitaux de Paris, Le Kremlin Bicêtre, Paris, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Davit-Spraul
authors.affiliation: Hepatology Unit, Saint Antoine Universitary Hospital, Faculty of Medicine Paris 6, University of Paris 6, Assistance Publique-Hôpitaux de Paris, Paris, France.
authors.forename: Filomena
authors.initials: F
authors.lastname: Conti
authors.affiliation: Pathology, Bicêtre Universitary Hospital, Faculty of Medicine Paris-Sud, University of Paris-Sud 11, Assistance Publique-Hôpitaux de Paris, Le Kremlin Bicêtre, Paris, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Guettier
authors.affiliation: INSERM, UMR-S1174, Hepatinov, University of Paris-Sud 11, Orsay, France.
authors.forename: Doris
authors.initials: D
authors.lastname: Cassio
authors.affiliation: Pediatric hepatology and pediatric liver transplantation unit and National Reference Centre for rare pediatric liver diseases, Bicêtre Universitary Hospital, Faculty of Medicine Paris-Sud, University of Paris-Sud 11, Assistance Publique-Hôpitaux de Paris, Le Kremlin Bicêtre, Paris, France.|INSERM, UMR-S1174, Hepatinov, University of Paris-Sud 11, Orsay, France.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Jacquemin
mesh_terms: D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters / Q000187:drug effects* / Q000235:genetics; D000818:Animals; D002478:Cells, Cultured; D002780:Cholestasis, Intrahepatic / Q000188:drug therapy* / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D058990:Molecular Targeted Therapy / Q000379:methods*; D020125:Mutation, Missense; D010654:Phenylbutyrates / Q000627:therapeutic use*; D051381:Rats; D012494:Sampling Studies; D013997:Time Factors; D014162:Transfection; D016896:Treatment Outcome
chemical_list: C093491:ABCB11 protein, human; D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters; D010654:Phenylbutyrates; C075773:4-phenylbutyric acid