Glutathione S-transferase m1 and t1 null genotypes increase susceptibility to idiosyncratic drug-induced liver injury.
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.
Lucena
M Isabel
MI
Servicio de Farmacología Clínica, Clinical Pharmacology Service, Liver Unit University Hospital School of Medicine, Málaga, Spain. lucena@uma.es
Andrade
Raúl J
RJ
Martínez
Carmen
C
Ulzurrun
Eugenia
E
García-Martín
Elena
E
Borraz
Yolanda
Y
Fernández
M Carmen
MC
Romero-Gomez
Manuel
M
Castiella
Agustin
A
Planas
Ramón
R
Costa
Joan
J
Anzola
Sandra
S
Agúndez
José A G
JA
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
D000658:Amoxicillin; D000900:Anti-Bacterial Agents; D019818:Clavulanic Acid; D005982:Glutathione Transferase; C413545:glutathione S-transferase T1