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A role for the pregnane X receptor in flucloxacillin‐induced liver injury
Author(s) -
Andrews Elise,
Armstrong Martin,
Tugwood Jonathan,
Swan Dan,
Glaves Philip,
Pirmohamed Munir,
Aithal Guruprasad P.,
Wright Matthew C.,
Day Christopher P.,
Daly Ann K.
Publication year - 2010
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.23549
Subject(s) - flucloxacillin , pregnane x receptor , pharmacology , agonist , medicine , biology , receptor , gene , nuclear receptor , transcription factor , genetics , staphylococcus aureus , bacteria
Drug‐induced liver injury (DILI) due to flucloxacillin is a rare but serious complication of treatment. There is some evidence that flucloxacillin is a human pregnane X receptor (PXR) agonist. This study was designed to investigate the relevance of PXR to flucloxacillin toxicity and to identify genes changing in expression in response to flucloxacillin. Changes in gene expression in human hepatocytes after treatment with 500 μM flucloxacillin for 72 hours were examined by expression microarray analysis. The ability of flucloxacillin to act as a PXR agonist was investigated with reporter gene experiments. Flucloxacillin DILI cases (n = 51), drug‐exposed controls without toxicity (n = 64), and community controls (n = 90) were genotyped for three common PXR polymorphisms. Luciferase reporter assays were used to assess the significance of a promoter region PXR polymorphism. Seventy‐two probe sets representing 50 different genes showed significant changes in expression of 1.2‐fold or higher. Most genes showing changes greater than 3‐fold were known to be rifampicin‐responsive, and this suggested a PXR‐dependent mode of regulation. Using a luciferase‐everted repeat separated by 6 base pairs element construct, we confirmed that flucloxacillin was a PXR agonist. We found a difference in the distribution of a PXR polymorphism (rs3814055; C‐25385T) between flucloxacillin DILI cases and controls with the CC genotype associated with an increased risk of disease (odds ratio = 3.37, 95% confidence interval = 1.55‐7.30, P = 0.0023). Reporter gene experiments showed lower promoter activity for the C allele than the T allele. Conclusion: Flucloxacillin is a PXR agonist at pharmacologically relevant concentrations, and a functionally significant upstream PXR polymorphism is a risk factor for flucloxacillin‐induced DILI. Hepatology 2010