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.
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 cholestasispatients than in drug-induced hepatocellular injurypatients and healthy controls (76 versus 50 and 59% in drug-induced cholestasispatients, drug-induced hepatocellular injurypatients and healthy controls, respectively; P<0.05). The in-vitro transport activity of the V444A and the D676YBSEP 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: Andrew Stolz; Victor Navarro; Paul H Hayashi; Robert J Fontana; Huiman X Barnhart; Jiezhun Gu; Naga P Chalasani; Maricruz M Vega; Herbert L Bonkovsky; Leonard B Seeff; Jose Serrano; Bharathi Avula; Ikhlas A Khan; Elizabeth T Cirulli; David E Kleiner; Jay H Hoofnagle Journal: Aliment Pharmacol Ther Date: 2019-04-01 Impact factor: 8.171
Authors: Tristan M Sissung; Phoebe A Huang; Ralph J Hauke; Edel M McCrea; Cody J Peer; Roberto H Barbier; Jonathan D Strope; Ariel M Ley; Mary Zhang; Julie A Hong; David Venzon; Jonathan P Jackson; Kenneth R Brouwer; Patrick Grohar; Jon Glod; Brigitte C Widemann; Theo Heller; David S Schrump; William D Figg Journal: Mol Pharmacol Date: 2019-06-07 Impact factor: 4.436
Authors: Richard H Ho; Brenda F Leake; Dawn M Kilkenny; Henriette E Meyer Zu Schwabedissen; Hartmut Glaeser; Deanna L Kroetz; Richard B Kim Journal: Pharmacogenet Genomics Date: 2010-01 Impact factor: 2.089