Role of chemical structures and the 1331T>C bile salt export pump polymorphism in idiosyncratic drug-induced liver injury
Article first published online: 23 MAY 2013
© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Volume 33, Issue 9, pages 1378–1385, October 2013
How to Cite
Liver Int. 2013; 33:1378–1385
- Issue published online: 8 SEP 2013
- Article first published online: 23 MAY 2013
- Accepted manuscript online: 17 APR 2013 08:51AM EST
- Manuscript Accepted: 14 APR 2013
- Manuscript Received: 11 FEB 2013
- Agencia Española del Medicamento
- Fondo de Investigación Sanitaria. Grant Number: 09/01384
- ABCB11 ;
- aromatic ring structure;
- canalicular transporter;
Background & Aims
Several pharmaceutical compounds have been shown to exert inhibitory effects on the bile salt export pump (BSEP) encoded by the ABCB11 gene. We analysed the combined effect on drug-induced liver injury (DILI) development of the ABCB11 1331T>C polymorphism and the presence of specific chemical moieties, with known BSEP inhibiting properties, in the causative drug.
Genotyping using a TaqMan 5′ allelic discrimination assay was performed in 188 Spanish DILI patients, 219 healthy controls and 91 sex-, age- and drug-matched controls. A chemical structure analysis was performed for each individual causative drug.
The CC genotype was significantly associated with hepatocellular damage [odds ratio (OR) = 2.1, P = 0.001], particularly in NSAID DILI cases (OR = 3.4, P = 0.007). In addition, the CC genotype was found to be significantly linked to DILI development from drugs causing <50% BSEP inhibition (OR = 1.8, Pc = 0.011). Of the BSEP inhibitory chemical moieties, 59% of the causative drugs contained a carbocyclic system with at least one aromatic ring, corresponding to 61% of the total cases. The C allele was significantly more frequent in DILI cases containing this chemical moiety, which appear to be conditioned on the ABCB11 1331T>C polymorphism in the absence of other BSEP inhibitory structures.
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.