Get access

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

Authors

  • Eugenia Ulzurrun,

    1. 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
    2. Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain
    Search for more papers by this author
  • Camilla Stephens,

    Corresponding author
    1. Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain
    • 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
    Search for more papers by this author
  • Esperanza Crespo,

    1. Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain
    2. Departamento de Farmacología, Facultad de Farmacia, Granada, Spain
    Search for more papers by this author
  • Francisco Ruiz-Cabello,

    1. Departamento de Bioquímica y Biología Molecular III/Inmunología, Hospital Universitario Virgen de las Nieves, Granada, Spain
    2. Red Genómica del Cáncer, Madrid, Spain
    Search for more papers by this author
  • Julia Ruiz-Nuñez,

    1. 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
    Search for more papers by this author
  • Pablo Saenz-López,

    1. Departamento de Bioquímica y Biología Molecular III/Inmunología, Hospital Universitario Virgen de las Nieves, Granada, Spain
    2. Red Genómica del Cáncer, Madrid, Spain
    Search for more papers by this author
  • Inmaculada Moreno-Herrera,

    1. 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
    2. Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain
    Search for more papers by this author
  • Mercedes Robles-Díaz,

    1. 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
    2. Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain
    Search for more papers by this author
  • Hacibe Hallal,

    1. Servicio de Aparato Digestivo, Hospital Morales Meseguer, Murcia, Spain
    Search for more papers by this author
  • José M. Moreno-Planas,

    1. Servicio de Aparato Digestivo, Complejo Hospitalario Universitario de Albacete, Albacete, Spain
    Search for more papers by this author
  • Maria R. Cabello,

    1. 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
    2. Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain
    Search for more papers by this author
  • M. Isabel Lucena,

    1. 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
    2. Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain
    Search for more papers by this author
  • Raúl J. Andrade

    1. 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
    2. Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain
    Search for more papers by this author

Correspondence

Camilla Stephens, Departamento de Farmacología, Facultad de Medicina, Boulevard Louis Pasteur, 32 Campus de Teatinos s/n, Málaga 29071, Spain

Tel: (+34) 952 133440

Fax: (+34) 952 131568

e-mail: cstephens@uma.es

Abstract

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.

Get access to the full text of this article

Ancillary