Background: Hyperbilirubinemia is a predictor of severe drug-induced liver injury (DILI). Hepatobiliary ATP-binding cassette (ABC) transporters play an important role in the transportation of many drugs and bilirubin; however, little is known about these transporters and the risk of DILI. The aim of this study was to explore associations between genetic variations in important ABC transporters and susceptibility to DILI, with a particular focus on hyperbilirubinemia.
Methods: A total of 200 patients with DILI and 200 healthy controls were enrolled as the training dataset. Another 106 patients with DILI were recruited as the validation dataset. They were genotyped for ABCB11 (BSEP) rs2287622, ABCB1 (MDR1) rs1128503, rs1045642, ABCB4 (MDR3) rs2230028, ABCC2 (MRP2) rs1885301, rs717620, rs2273697, rs3740066 and rs8187710 using polymerase chain reaction-based TaqMan genotyping assays.
Results: There were no statistical differences in any of the nine ABC transporter single nucleotide polymorphisms between the DILI and control groups. However, in the DILI group, the patients with hyperbilirubinemia had a higher frequency of the ABCC2 rs717620 C/T and T/T genotypes than those without hyperbilirubinemia (44.2% vs 20.2%, p = 0.001). After adjusting for other confounding factors, the ABCC2 rs717620 T variant was still associated with an increased risk of hyperbilirubinemia (adjusted odds ratio [OR]: 3.83, 95% confidence interval [CI]: 1.73-8.48, p = 0.001). This association was confirmed by the validation dataset (adjusted OR: 3.92, 95% CI: 1.42-10.81, p = 0.015). We also found that the mortality group had higher frequencies of the ABCC2 (MRP2) rs717620 C/T and T/T genotypes than the survival group (50.0% vs 27.9%, p = 0.048).
Conclusion: Carriage of the ABCC2 (MRP2) rs717620 T variant may increase the risk of hyperbilirubinemia and mortality in patients with DILI. Screening for this variant may help to prevent and mitigate drug-induced hyperbilirubinemia.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1097/JCMA.0000000000000470 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Functional Characterization and In Silico Prediction Tools Improve the Pathogenicity Prediction of Novel Bile Acid Transporter Variants.
Clin Genet
January 2025
Human Molecular Genetics Group, National Health Commission (NHC), Key Laboratory of Molecular Probes and Targeted Diagnosis and Therapy, Harbin Medical University, Harbin, China.
The pathogenicity of cholestatic liver diseases (CLDs) remains insufficiently characterized, hindering definitive diagnosis and timely treatment. The aim of this study was to improve the pathogenicity prediction of novel bile acid (BA) transporter variants in patients with CLDs. We analyzed the clinical characteristics and genetic profiles of a CLD cohort (n = 57) using multiple in silico tools and in vitro functional assays.
View Article and Find Full Text PDFStructural basis for the transport and regulation mechanism of the multidrug resistance-associated protein 2.
Nat Commun
January 2025
Laboratory of Membrane Biology and Biophysics, The Rockefeller University, New York, NY, USA.
Multidrug resistance-associated protein 2 (MRP2) is an ATP-powered exporter important for maintaining liver homeostasis and a potential contributor to chemotherapeutic resistance. Using cryogenic electron microscopy (cryo-EM), we determine the structures of human MRP2 in three conformational states: an autoinhibited state, a substrate-bound pre-translocation state, and an ATP-bound post-translocation state. In the autoinhibited state, the cytosolic regulatory (R) domain plugs into the transmembrane substrate-binding site and extends into the cytosol to form a composite ATP-binding site at the surface of nucleotide-binding domain 2.
View Article and Find Full Text PDFEfflux and uptake transport and gut microbial reactivation of raloxifene glucuronides.
Basic Clin Pharmacol Toxicol
January 2025
Division of Pharmaceutical Biosciences, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland.
Raloxifene has low bioavailability due to extensive glucuronidation in the intestine and the liver, and its pharmacokinetics is associated with high intra- and interindividual variability. Some of this variability could be explained by the enterohepatic recycling of raloxifene, which is driven by transporter-mediated uptake and efflux and gut microbial deglucuronidation of raloxifene glucuronides. These individual processes involved in raloxifene disposition, however, have not been characterized in full detail.
View Article and Find Full Text PDFUnsymmetrical Bisacridines' Interactions with ABC Transporters and Their Cellular Impact on Colon LS 174T and Prostate DU 145 Cancer Cells.
Molecules
November 2024
Department of Pharmaceutical Technology and Biochemistry, Faculty of Chemistry, Gdańsk University of Technology, Gabriela Narutowicza Str. 11/12, 80-233 Gdańsk, Poland.
Multidrug resistance (MDR) is a process that constitutes a significant obstacle to effective anticancer therapy. Here, we examined whether unsymmetrical bisacridines (UAs) are substrates for ABC transporters and can influence their expression in human colon LS 174T and prostate DU 145 cancer cells. Moreover, we investigated the cytotoxicity and the cellular response induced by UAs in these cells.
View Article and Find Full Text PDFMitigation of polystyrene microplastic-induced hepatotoxicity in human hepatobiliary organoids through bile extraction.
Ecotoxicol Environ Saf
December 2024
Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki 852-8102, Japan. Electronic address:
Background & Aims: Polystyrene microplastics (PS-MPs) are pervasive in our daily life and can be ingested by the human body through bioaccumulation, causing organ damage, especially liver damage. However, the effect of PS-MPs bioaccumulation on human hepatotoxicity and their metabolism remains unclear. Recent studies have demonstrated that PS-MPs cause lipid and bile acid metabolism disorders.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!