title: Glutathione S-transferase m1 and t1 null genotypes increase susceptibility to idiosyncratic drug-induced liver injury.
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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Servicio de Farmacología Clínica, Clinical Pharmacology Service, Liver Unit University Hospital School of Medicine, Málaga, Spain. lucena@uma.es
authors.forename: M Isabel
authors.initials: MI
authors.lastname: Lucena
authors.forename: Raúl J
authors.initials: RJ
authors.lastname: Andrade
authors.forename: Carmen
authors.initials: C
authors.lastname: Martínez
authors.forename: Eugenia
authors.initials: E
authors.lastname: Ulzurrun
authors.forename: Elena
authors.initials: E
authors.lastname: García-Martín
authors.forename: Yolanda
authors.initials: Y
authors.lastname: Borraz
authors.forename: M Carmen
authors.initials: MC
authors.lastname: Fernández
authors.forename: Manuel
authors.initials: M
authors.lastname: Romero-Gomez
authors.forename: Agustin
authors.initials: A
authors.lastname: Castiella
authors.forename: Ramón
authors.initials: R
authors.lastname: Planas
authors.forename: Joan
authors.initials: J
authors.lastname: Costa
authors.forename: Sandra
authors.initials: S
authors.lastname: Anzola
authors.forename: José A G
authors.initials: JA
authors.lastname: Agúndez
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000658:Amoxicillin / Q000009:adverse effects; D000900:Anti-Bacterial Agents / Q000009:adverse effects; D056486:Chemical and Drug Induced Liver Injury; D019818:Clavulanic Acid / Q000009:adverse effects; D005260:Female; D017353:Gene Deletion; D020022:Genetic Predisposition to Disease; D005838:Genotype; D005982:Glutathione Transferase / Q000172:deficiency / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D008107:Liver Diseases / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D012737:Sex Factors
chemical_list: D000658:Amoxicillin; D000900:Anti-Bacterial Agents; D019818:Clavulanic Acid; D005982:Glutathione Transferase; C413545:glutathione S-transferase T1