Mutations and polymorphisms in the bile salt export pump and the multidrug resistance protein 3 associated with drug-induced liver injury.

Abstract

OBJECTIVES:

Increasing evidence suggests that a genetically determined functional impairment of the hepatocellular efflux transporters bile salt export pump (BSEP, ABCB11) and multidrug resistance protein 3 (MDR3, ABCB4) play a pathophysiological role in the development of drug-induced liver injury. The aim of this study was therefore to describe the extent of genetic variability in ABCB11 and ABCB4 in patients with drug-induced liver injury and to in vitro functionally characterize newly detected ABCB11 mutations and polymorphisms.

METHODS:

ABCB11 and ABCB4 were sequenced in 23 patients with drug-induced cholestasis and 13 patients with drug-induced hepatocellular injury. Ninety-five healthy Caucasians served as the control group. Reference and mutant BSEP were expressed in Sf9 cells and ATP-dependent transport of [H]-taurocholate was measured in a rapid filtration assay.

RESULTS:

Four highly conserved nonsynonymous mutations were specific for drug-induced liver injury [ABCB11: D676Y (drug-induced cholestasis) and G855R (drug-induced cholestasis); ABCB4: I764L (drug-induced cholestasis) and L1082Q (drug-induced hepatocellular injury)]. Furthermore, a polymorphism in exon 13 of ABCB11 (V444A), which is associated with decreased hepatic BSEP expression was significantly more frequent in drug-induced cholestasis patients than in drug-induced hepatocellular injury patients and healthy controls (76 versus 50 and 59% in drug-induced cholestasis patients, drug-induced hepatocellular injury patients and healthy controls, respectively; P<0.05). The in-vitro transport activity of the V444A and the D676Y BSEP constructs was similar, whereas the G855R mutation was nonfunctional.

CONCLUSION:

In summary, our data support a role of ABCB11 and ABCB4 mutations and polymorphisms in drug-induced cholestasis. Genotyping of selected patients with acquired cholestasis might help to identify individuals with a genetic predisposition.

• Authors: Carmen Lang, Yvonne Meier, Bruno Stieger, Ulrich Beuers, Thomas Lang, Reinhold Kerb, Gerd A Kullak-Ublick, Peter J Meier, Christiane Pauli-Magnus
• Journal: Pharmacogenetics and genomics (Pharmacogenet Genomics) Vol. 17 Issue 1 Pg. 47-60 (Jan 2007) ISSN: 1744-6872 [Print] United States
• PMID: 17264802 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• ABCB11 protein, human
• ATP Binding Cassette Transporter, Subfamily B
• ATP Binding Cassette Transporter, Subfamily B, Member 11
• ATP-Binding Cassette Transporters
• Taurocholic Acid
• multidrug resistance protein 3

Topics

• ATP Binding Cassette Transporter, Subfamily B (genetics)
• ATP Binding Cassette Transporter, Subfamily B, Member 11
• ATP-Binding Cassette Transporters (genetics)
• Adolescent
• Adult
• Aged
• Aged, 80 and over
• Amino Acid Sequence
• Chemical and Drug Induced Liver Injury
• Cholestasis (chemically induced, genetics, pathology)
• Female
• Genetic Predisposition to Disease
• Humans
• Liver Diseases (genetics, pathology)
• Male
• Middle Aged
• Molecular Sequence Data
• Mutation
• Polymorphism, Genetic
• Protein Structure, Secondary
• Taurocholic Acid (metabolism)
• White People