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

• Published in: Liver international Vol. 33; no. 9; pp. 1378 - 1385
• Main Authors: Ulzurrun, Eugenia, Stephens, Camilla, Crespo, Esperanza, Ruiz-Cabello, Francisco, Ruiz-Nuñez, Julia, Saenz-López, Pablo, Moreno-Herrera, Inmaculada, Robles-Díaz, Mercedes, Hallal, Hacibe, Moreno-Planas, José M., Cabello, Maria R., Lucena, M. Isabel, Andrade, Raúl J.
• Format: Journal Article
• Language: English
• Published: United States Blackwell Publishing Ltd 01-10-2013
• Subjects: ABCB11; Acids, Carbocyclic - chemistry; aromatic ring structure; ATP Binding Cassette Subfamily B Member 11; ATP-Binding Cassette Transporters - genetics; canalicular transporter; Chemical and Drug Induced Liver Injury - genetics; Drug-Related Side Effects and Adverse Reactions - genetics; Female; Gene Frequency; Genetic Predisposition to Disease - genetics; Genotype; hepatotoxicity; Humans; Hydrocarbons, Aromatic - chemistry; Male; Odds Ratio; Pharmaceutical Preparations - chemistry; pharmacogenetics; Polymorphism, Single Nucleotide - genetics; Quantitative Structure-Activity Relationship; Spain; canalicular transporter; aromatic ring structure; ABCB11; hepatotoxicity; pharmacogenetics
• ISSN: 1478-3223; 1478-3231
• DOI: 10.1111/liv.12193

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.
Methods
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.
Results
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.
Conclusion
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.