title: Role of chemical structures and the 1331T>C bile salt export pump polymorphism in idiosyncratic drug-induced liver injury.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: S Farmacología Clínica and Unidad de Hepatogía, Hospital Universitario Virgen de la Victoria, Facultad de Medicina, Universidad de Málaga, Instituto de Investigación Biomédica de Málaga (IBIMA), Málaga, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain.
authors.forename: Eugenia
authors.initials: E
authors.lastname: Ulzurrun
authors.forename: Camilla
authors.initials: C
authors.lastname: Stephens
authors.forename: Esperanza
authors.initials: E
authors.lastname: Crespo
authors.forename: Francisco
authors.initials: F
authors.lastname: Ruiz-Cabello
authors.forename: Julia
authors.initials: J
authors.lastname: Ruiz-Nuñez
authors.forename: Pablo
authors.initials: P
authors.lastname: Saenz-López
authors.forename: Inmaculada
authors.initials: I
authors.lastname: Moreno-Herrera
authors.forename: Mercedes
authors.initials: M
authors.lastname: Robles-Díaz
authors.forename: Hacibe
authors.initials: H
authors.lastname: Hallal
authors.forename: José M
authors.initials: JM
authors.lastname: Moreno-Planas
authors.forename: Maria R
authors.initials: MR
authors.lastname: Cabello
authors.forename: M Isabel
authors.initials: MI
authors.lastname: Lucena
authors.forename: Raúl J
authors.initials: RJ
authors.lastname: Andrade
mesh_terms: D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000146:Acids, Carbocyclic / Q000737:chemistry; D056486:Chemical and Drug Induced Liver Injury / Q000235:genetics*; D064420:Drug-Related Side Effects and Adverse Reactions / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006801:Humans; D006841:Hydrocarbons, Aromatic / Q000737:chemistry; D008297:Male; D016017:Odds Ratio; D004364:Pharmaceutical Preparations / Q000737:chemistry*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D021281:Quantitative Structure-Activity Relationship; D013030:Spain
chemical_list: C093491:ABCB11 protein, human; D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters; D000146:Acids, Carbocyclic; D006841:Hydrocarbons, Aromatic; D004364:Pharmaceutical Preparations
keywords: ABCB11; aromatic ring structure; canalicular transporter; hepatotoxicity; pharmacogenetics