Role of chemical structures and the 1331T&gt;C bile salt export pump polymorphism in idiosyncratic drug‐induced liver injury

Ulzurrun, Eugenia; Stephens, Camilla; Crespo, Esperanza; Ruiz‐Cabello, Francisco; Ruiz-Nuñez, Julia; Sáenz-López, Pablo; Moreno-Herrera, Inmaculada; Robles‐Díaz, Mercedes; Hallal, Hacibe; Planas, J.M. Moreno; Cabello, M.R.; Lucena, M. Isabel; Andrade, Raúl J.

doi:10.1111/liv.12193

Cited by 41 publications

(35 citation statements)

References 27 publications

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“…Similar differences were observed in studies of ICP [n = 491, 67% of patients versus 54% of controls, P , 0.001 (Dixon et al, 2009); n = 42, 76% of patients versus 51% of controls, P = 0.0007 (Meier et al, 2008)]. A Spanish study reported that the C-allele was associated with an increased risk of developing DILI; however, this association was observed only among those with hepatocellular liver injury (Ulzurrun et al, 2013). Recently, Dixon et al (2014) demonstrated through a conditional analysis that rs3815676 and rs7577650, rather than rs2287622 (1331T.C), associated significantly with ICP in western Europeans.…”

Section: Discussionsupporting

confidence: 53%

No Contribution of the ABCB11 p.444A Polymorphism in Japanese Patients with Drug-Induced Cholestasis

et al. 2015

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European studies have revealed that the ABCB11 c.1331T>C (V444A) polymorphism (rs2287622) C-allele frequency is higher among patients with drug-induced cholestasis. Given the low incidence of this disease, however, this association has not been sufficiently elucidated. We aimed to investigate the significance of this polymorphism in Japanese patients. We determined ABCB11 V444A polymorphism frequencies and HLA genotypes in two independent drug-induced cholestasis cohorts. Expression and taurocholate transport activity of proteins from 444A variants were analyzed using Madin-Darby canine kidney II cells. In cohort 1 (n = 40), the V444A polymorphism C-allele frequency (66%) was lower than that in controls (n = 190, 78%), but this difference was not significant (P = 0.09). In cohort 2 (n = 119), comprising patients with cholestatic (n = 19), hepatocellular (n = 74), and mixed (n = 26) liver injuries, the C-allele frequency was lower among patients with cholestatic liver injury (68%) than among those with hepatocellular (75%) or mixed liver injury (83%), although this difference was not significant. In cohort 1, HLA-A*0201 was observed more frequently in patients (22%) than in controls [11%; P = 0.003; odds ratio, 2.4 (95% confidence interval, 1.4-4.0)]. Taurocholate transport activity of 444A-encoded protein was significantly lower than that of 444V-encoded protein (81% of 444V, P < 0.05) because of the reduced protein stability. In conclusion, ABCB11 444A had slightly reduced transport activity, but it did not contribute to the occurrence of drug-induced cholestasis in Japanese patients. Therefore, genetic susceptibility to acquired cholestasis may differ considerably by ethnicity.

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Section: Discussionsupporting

confidence: 53%

No Contribution of the ABCB11 p.444A Polymorphism in Japanese Patients with Drug-Induced Cholestasis

et al. 2015

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“…Specifically, focus has shifted to BSEP inhibition as a cause of drug-induced cholestasis (DIC) and possibly drug-induced liver injury (DILI) (Stepan et al, 2011;Kubitz et al, 2012;Bjornsson and Jonasson, 2013;Yang et al, 2013). Interest in BSEP (ABC11) has been fueled also by reports that subjects carrying certain loss-of-function/expression ABC11 alleles are predisposed to DILI (Ulzurrun et al, 2013). As a result, a considerable amount of effort has been made to set up high-throughput in vitro inhibition screens in an attempt to mitigate drug interactions involving BSEP inhibition and DIC (Morgan et al, 2010;Dawson et al, 2012;Warner et al, 2012;Pedersen et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

Drug-Induced Perturbations of the Bile Acid Pool, Cholestasis, and Hepatotoxicity: Mechanistic Considerations beyond the Direct Inhibition of the Bile Salt Export Pump

et al. 2013

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The bile salt export pump (BSEP) is located on the canalicular plasma membrane of hepatocytes and plays an important role in the biliary clearance of bile acids (BAs). Therefore, any drug or new chemical entity that inhibits BSEP has the potential to cause cholestasis and possibly liver injury. In reality, however, one must consider the complexity of the BA pool, BA enterohepatic recirculation (EHR), extrahepatic (renal) BA clearance, and the interplay of multiple participant transporters and enzymes (e.g., sulfotransferase 2A1, multidrug resistance-associated protein 2, 3, and 4). Moreover, BAs undergo extensive enzyme-catalyzed amidation and are subjected to metabolism by enterobacteria during EHR. Expression of the various enzymes and transporters described above is governed by nuclear hormone receptors (NHRs) that mount an adaptive response when intracellular levels of BAs are increased. The intracellular trafficking of transporters, and their ability to mediate the vectorial transport of BAs, is governed by specific kinases also. Finally, bile flow, micelle formation, canalicular membrane integrity, and BA clearance can be influenced by the inhibition of multidrug resistant protein 3-or ATPase-aminophospholipid transporter-mediated phospholipid flux. Consequently, when screening compounds in a discovery setting or conducting mechanistic studies to address clinical findings, one has to consider the direct (inhibitory) effect of the parent drug and metabolites on multiple BA transporters, as well as inhibition of BA sulfation and amidation and NHR function. Vectorial BA transport, in addition to BA EHR and homoeostasis, could also be impacted by drug-dependent modulation of kinases and enterobacteria.

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“…However, there is increasing awareness that the current experimental animal models are not predictive for the human clinical situation. This discrepancy can be due to species differences in bile acid pool composition (García-Cañaveras et al, 2012;Setchell et al, 1997), in individual bile acid concentrations and in abundance and functionality of the transporters and enzymes involved in bile acid handling, as well as in their susceptibility for interference by the drug (Ulzurrun et al, 2013). Moreover, the animals used for drug testing are genetically more uniform than the human patient population and this can result in skewed results.…”

Section: Introductionmentioning

confidence: 97%

“…As prototypical BSEP inhibiting drugs we used glibenclamide and cyclosporin A. Both drugs have been associated with cholestatic DILI and are inhibitors of BSEP (Byrne et al, 2002;Goodman et al, 1987;Morgan et al, 2010;van Basten et al, 1992;Varma et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

Development of a mechanistic biokinetic model for hepatic bile acid handling to predict possible cholestatic effects of drugs

Notenboom

Weigand

Proost

et al. 2018

European Journal of Pharmaceutical Sciences

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A B S T R A C TDrug-induced liver injury (DILI) is a common reason for drug withdrawal from the market. An important cause of DILI is drug-induced cholestasis. One of the major players involved in drug-induced cholestasis is the bile salt efflux pump (BSEP; ABCB11). Inhibition of BSEP by drugs potentially leads to cholestasis due to increased (toxic) intrahepatic concentrations of bile acids with subsequent cell injury. In order to investigate the possibilities for in silico prediction of cholestatic effects of drugs, we developed a mechanistic biokinetic model for human liver bile acid handling populated with human in vitro data. For this purpose we considered nine groups of bile acids in the human bile acid pool, i.e. chenodeoxycholic acid, deoxycholic acid, the remaining unconjugated bile acids and the glycine and taurine conjugates of each of the three groups. Michaelis-Menten kinetics of the human uptake transporter Na + -taurocholate cotransporting polypeptide (NTCP; SLC10A1) and BSEP were measured using NTCP-transduced HEK293 cells and membrane vesicles from BSEP-overexpressing HEK293 cells. For in vitro-in vivo scaling, transporter abundance was determined by LC-MS/MS in these HEK293 cells and vesicles as well as in human liver tissue. Other relevant human kinetic parameters were collected from literature, such as portal bile acid levels and composition, bile acid synthesis and amidation rate. Additional empirical scaling was applied by increasing the excretion rate with a factor 2.4 to reach near physiological steady-state intracellular bile acid concentrations (80 μM) after exposure to portal vein bile acid levels. Simulations showed that intracellular bile acid concentrations increase 1.7 fold in the presence of the BSEP inhibitors and cholestatic drugs cyclosporin A or glibenclamide, at intrahepatic concentrations of 6.6 and 20 μM, respectively. This simplified model provides a tool for a first indication whether drugs at therapeutic concentrations might cause cholestasis by inhibiting BSEP.

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Role of chemical structures and the 1331T>C bile salt export pump polymorphism in idiosyncratic drug‐induced liver injury

Abstract: Patients carrying the C allele in the ABCB11 1331T>C polymorphism are at increased risk of developing hepatocellular type of DILI, when taking drugs containing a carbocyclic system with aromatic rings.

Cited by 41 publications

References 27 publications

No Contribution of the ABCB11 p.444A Polymorphism in Japanese Patients with Drug-Induced Cholestasis

No Contribution of the ABCB11 p.444A Polymorphism in Japanese Patients with Drug-Induced Cholestasis

Drug-Induced Perturbations of the Bile Acid Pool, Cholestasis, and Hepatotoxicity: Mechanistic Considerations beyond the Direct Inhibition of the Bile Salt Export Pump

Development of a mechanistic biokinetic model for hepatic bile acid handling to predict possible cholestatic effects of drugs

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