Targeted pharmacotherapy in progressive familial intrahepatic cholestasis type 2: Evidence for improvement of cholestasis with 4-phenylbutyrate.

Abstract

UNLABELLED:

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.

CONCLUSION:

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: Emmanuel Gonzales, Brigitte Grosse, Brice Schuller, Anne Davit-Spraul, Filomena Conti, Catherine Guettier, Doris Cassio, Emmanuel Jacquemin
• Journal: Hepatology (Baltimore, Md.) (Hepatology) Vol. 62 Issue 2 Pg. 558-66 (Aug 2015) ISSN: 1527-3350 [Electronic] United States
• PMID: 25716872 (Publication Type: Journal Article)
• Copyright: © 2015 by the American Association for the Study of Liver Diseases.

Chemical References

• ABCB11 protein, human
• ATP Binding Cassette Transporter, Subfamily B, Member 11
• ATP-Binding Cassette Transporters
• Phenylbutyrates
• 4-phenylbutyric acid

Topics

• ATP Binding Cassette Transporter, Subfamily B, Member 11
• ATP-Binding Cassette Transporters (drug effects, genetics)
• Animals
• Cells, Cultured
• Cholestasis, Intrahepatic (drug therapy, pathology)
• Dose-Response Relationship, Drug
• Drug Administration Schedule
• Female
• Follow-Up Studies
• Humans
• Male
• Molecular Targeted Therapy (methods)
• Mutation, Missense
• Phenylbutyrates (therapeutic use)
• Rats
• Sampling Studies
• Time Factors
• Transfection
• Treatment Outcome