Glutathione S-transferase m1 and t1 null genotypes increase susceptibility to idiosyncratic drug-induced liver injury

Authors

  • M. Isabel Lucena,

    1. Servicio de Farmacología Clínica (Clinical Pharmacology Service), (Liver Unit University Hospital School of Medicine) Málaga Spain
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    • fax: (34)-952-131568

  • Raúl J. Andrade,

    1. Unidad de Hepatología, Hospital Universitario Virgen de la Victoria, Facultad de Medicina (Liver Unit University Hospital, School of Medicine), Málaga, Spain
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  • Carmen Martínez,

    1. Departamento de Farmacología, Facultad de Medicina Universidad de Extremadura (Department of Pharmacology, School of Medicine, Extremadura University), Badajoz, Spain
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  • Eugenia Ulzurrun,

    1. Servicio de Farmacología Clínica (Clinical Pharmacology Service), (Liver Unit University Hospital School of Medicine) Málaga Spain
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  • Elena García-Martín,

    Corresponding author
    1. Departamento de Bioquímica and Biología Molecular y Genética, Facultad de Ciencias, Universidad de Extremadura (Department of Biochemistry and Molecular Biology and Genetics, School of Sciences, Extremadura University), Badajoz, Spain
    • Servicio de Farmacología Clínica, Departamento de Farmacología, Facultad de Medicina, Boulevard Louis Pasteur, 32, Campus de Teatinos s/n, 29071 Málaga, Spain
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  • Yolanda Borraz,

    1. Servicio de Farmacología Clínica (Clinical Pharmacology Service), (Liver Unit University Hospital School of Medicine) Málaga Spain
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  • M. Carmen Fernández,

    1. Servicio de Farmacologia Clínica y Aparato Digestivo, Hospital Torrecárdenas (Clinical Pharmacology and Gastroenterology Service, Hospital Torrecardenas), Almeria, Spain
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  • Manuel Romero-Gomez,

    1. Servicio de Aparato Digestivo, H Valme (Gastroenterology Service, University Hospital Virgen de Valme), Sevilla, Spain
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  • Agustin Castiella,

    1. Servicio de Aparato Digestivo, H Mendaro (Gastroenterology Service, Hospital Mendaro), Guipúzcoa, Spain
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  • Ramón Planas,

    1. Servicio de Gastroenterología y Farmacología Clínica, H Germans Trias y Pujol (Gastroenterology and Clinical Pharmacology Service, Hospital Germans Trias y Pujol), Badalona, Spain
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  • Joan Costa,

    1. Servicio de Gastroenterología y Farmacología Clínica, H Germans Trias y Pujol (Gastroenterology and Clinical Pharmacology Service, Hospital Germans Trias y Pujol), Badalona, Spain
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  • Sandra Anzola,

    1. Servicio de Gastroenterología y Farmacología Clínica, H Germans Trias y Pujol (Gastroenterology and Clinical Pharmacology Service, Hospital Germans Trias y Pujol), Badalona, Spain
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  • José A. G. Agúndez

    1. Departamento de Farmacología, Facultad de Medicina Universidad de Extremadura (Department of Pharmacology, School of Medicine, Extremadura University), Badajoz, Spain
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  • Potential conflict of interest: Nothing to report.

Abstract

Individual vulnerability to drug-induced liver injury (DILI) might result from deficiencies in the detoxification process, which determines the level of exposure to the reactive metabolite. We evaluated whether a genetically determined reduction in the ability to detoxify electrophilic compounds, such as that expected among individuals with glutathione S-transferase (GST) null genotypes, might play a role in determining the risk for DILI and its clinical expression. Genomic DNA from 154 patients (74 men, 80 women; mean age, 53 years) with a diagnosis of DILI as assessed with the Council for International Organizations of Medical Science scale and 250 sex- and age-matched healthy controls were analyzed. A multiplex polymerase chain reaction–based method was used to detect GSTM1 and GSTT1 gene deletions. Carriers of double GSTT1-M1 null genotypes had a 2.70-fold increased risk of developing DILI compared with noncarriers (odds ratio 2.70, 95% confidence interval 1.45-5.03; P = 0.003). The odds ratio for DILI patients receiving antibacterials, and NSAIDs were 3.52 (P = 0.002), and 5.61 (P = 0.001), respectively. Patients with amoxicillin-clavulanate hepatotoxicity (n = 32) had a 2.81-fold increased risk (P = 0.037). Patients classified by the combined GSTT1 and GSTM1 null genotypes did not differ with regard to the type of injury, clinical presentation, or outcome, except for the predominance of women in the combined null genotype (P < 0.001). Conclusion: The double-null genotype for GSTT1 and GSTM1 might play a role in determining the susceptibility to develop DILI, as a general mechanism that occurs regardless of the type of drug involved, and predominantly in women. (HEPATOLOGY 2008;48:588–596.)

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