BSEP inhibition – In vitro screens to assess cholestatic potential of drugs

Kis, Emese; Ioja, Enikő; Rajnai, Zsuzsa; Jani, Márton; Méhn, Dóra; Herédi-Szabó, Krisztina; Krajcsi, Péter

doi:10.1016/j.tiv.2011.11.002

Cited by 47 publications

(42 citation statements)

References 42 publications

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“…While this protein is also found in many cell types, porphyrin release is the most common function found in hepatocytes [92, 93]. BSEP is a protein localized to hepatocytes that functions in the transport of bile salts into the bile canaliculi [94]. As a result, BSEP is an important regulatory in bile flow.…”

Section: Mechanisms For Idiosyncratic Hepatotoxicitymentioning

confidence: 99%

“…Mutations in ABC transporters mean that metabolized drugs cannot leave the hepatocytes, leading to impaired canalicular bile flow. This generally manifests in the form of cholestasis and fatty liver disease [94, 95]. MDR1, BSEP, BCRP, and MRP2 all have polymorphisms that have been associated with idiosyncratic ADRs.…”

Section: Mechanisms For Idiosyncratic Hepatotoxicitymentioning

confidence: 99%

“…Common BSEP assays include the vesicular transport assay (VTA) and the ATPase assay [94], both of which rely on the presence of ATP as a to drive the protein function and hence the assay. Because both assays rely on ATP, this makes VTA and the ATPase assay also suitable for ABC transporter proteins.…”

Section: Assays Detecting Susceptibility For Idiosyncratic Reactionsmentioning

confidence: 99%

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Idiosyncratic Drug-Induced Liver Injury (IDILI): Potential Mechanisms and Predictive Assays

Roth

Lee

2017

BioMed Research International

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Idiosyncratic drug-induced liver injury (IDILI) is a significant source of drug recall and acute liver failure (ALF) in the United States. While current drug development processes emphasize general toxicity and drug metabolizing enzyme- (DME-) mediated toxicity, it has been challenging to develop comprehensive models for assessing complete idiosyncratic potential. In this review, we describe the enzymes and proteins that contain polymorphisms believed to contribute to IDILI, including ones that affect phase I and phase II metabolism, antioxidant enzymes, drug transporters, inflammation, and human leukocyte antigen (HLA). We then describe the various assays that have been developed to detect individual reactions focusing on each of the mechanisms described in the background. Finally, we examine current trends in developing comprehensive models for examining these mechanisms. There is an urgent need to develop a panel of multiparametric assays for diagnosing individual toxicity potential.

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Section: Mechanisms For Idiosyncratic Hepatotoxicitymentioning

confidence: 99%

Section: Mechanisms For Idiosyncratic Hepatotoxicitymentioning

confidence: 99%

Section: Assays Detecting Susceptibility For Idiosyncratic Reactionsmentioning

confidence: 99%

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Idiosyncratic Drug-Induced Liver Injury (IDILI): Potential Mechanisms and Predictive Assays

Roth

Lee

2017

BioMed Research International

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“…Kis et al . () have summarized appropriate in vitro methods that could predict BSEP–drug candidate interactions in humans.…”

Section: Developments In Safety Testing Paradigmmentioning

confidence: 99%

Drug safety testing paradigm, current progress and future challenges: an overview

Ahuja

Sharma

2013

J. Appl. Toxicol.

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Early assessment of the toxicity potential of new molecules in pharmaceutical industry is a multi-dimensional task involving predictive systems and screening approaches to aid in the optimization of lead compounds prior to their entry into development phase. Due to the high attrition rate in the pharma industry in last few years, it has become imperative for the nonclinical toxicologist to focus on novel approaches which could be helpful for early screening of drug candidates. The need is that the toxicologists should change their classical approach to a more investigative approach. This review discusses the developments that allow toxicologists to anticipate safety problems and plan ways to address them earlier than ever before. This includes progress in the field of in vitro models, surrogate models, molecular toxicology, 'omics' technologies, translational safety biomarkers, stem-cell based assays and preclinical imaging. The traditional boundaries between teams focusing on efficacy/ safety and preclinical/ clinical aspects in the pharma industry are disappearing, and translational research-centric organizations with a focused vision of bringing drugs forward safely and rapidly are emerging. Today's toxicologist should collaborate with medicinal chemists, pharmacologists, and clinicians and these value-adding contributions will change traditional toxicologists from side-effect identifiers to drug development enablers.

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“…7 Intrahepatic accumulation of drug or cytotoxic bile acids caused by drug interference of either bile formation or bile flow is one of the major mechanisms contributing to DILI. 8 Both hepatic sinusoidal uptake transporters and canalicular efflux transporters have essential roles in mediating the translocation of drug and bile salts from the blood to the hepatocytes and from the hepatocytes to the canalicular space, respectively; the latter is considered to be a rate-controlling step of vectorial transport. 9 Drugs can potentially cause intrahepatic cholestasis by modulating bile formation at many levels.…”

Section: Introductionmentioning

confidence: 99%

High-Content Imaging in Human and Rat Hepatocytes Using the Fluorescent Dyes CLF and CMFDA Is Not Specific Enough to Assess BSEP/Bsep and/or MRP2/Mrp2 Inhibition by Cholestatic Drugs

QiuLuping

FinleyJames

TaimiMohammed

et al. 2015

Applied In Vitro Toxicology

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Inhibition of hepatic efflux transporters (BSEP, MRP2) is one of the important mechanisms in drug-induced liver injury and in particular cholestasis. The inhibitory effect of compounds on these two hepatic transporters is commonly delineated using inverted membrane vesicles from Sf9 insect cells overexpressing the BSEP or MRP2 protein. However, due to lack of bioactivation and metabolism of the compound, and the lack of the expression and functionality of other sinusoidal efflux and uptake transporters in the cell-free assay system, it is difficult to fully understand the role of a given hepatic transporter in cholestasis. Therefore, our aim was to characterize and develop a competent cell-based bile canalicular imaging assay for measuring the overall inhibitory effects of compounds on biliary transport. Since species differences have been reported for some compounds, we developed the assay using both rat and human hepatocytes. Two fluorescent dyes, cholyl-lysyl-fluorescein (CLF) and carboxymethyl flourescein diacetate (CMFDA), have been reported in the literature to measure BSEP and MRP2 inhibition. We show in our study that neither CLF nor CMFDA is a specific substrate for either BSEP/Bsep or MRP2/ Mrp2 as demonstrated by generating K m values for each transporter. Most of the drugs tested inhibited CLF accumulation and exhibited less potency toward CMFDA accumulation in hepatocytes. We found the highest concordance between IC 50 values for inhibition of CLF accumulation in human hepatoyctes and IC 50 values generated in the human BSEP vesicle assay. This suggests that the human vesicle-based assays could suffice as a primary screen to avoid future potential human liver injury.

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BSEP inhibition – In vitro screens to assess cholestatic potential of drugs

Cited by 47 publications

References 42 publications

Idiosyncratic Drug-Induced Liver Injury (IDILI): Potential Mechanisms and Predictive Assays

Idiosyncratic Drug-Induced Liver Injury (IDILI): Potential Mechanisms and Predictive Assays

Drug safety testing paradigm, current progress and future challenges: an overview

High-Content Imaging in Human and Rat Hepatocytes Using the Fluorescent Dyes CLF and CMFDA Is Not Specific Enough to Assess BSEP/Bsep and/or MRP2/Mrp2 Inhibition by Cholestatic Drugs

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