No abstract

on behalf of the Spanish Group for the Study of Drug-Induced Liver Disease 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 sexand 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 doublenull 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.) I diosyncratic drug-induced liver injury (DILI) is a clinical challenge due to the rarity of its diagnosis and the lack of a gold standard, which makes determination of causality difficult. 1 Efforts to enhance the identification of adverse hepatic reactions and to obtain reliable information are being made in the setting of collaborative networks. 2,3 In spite of these efforts, the genetic and environmental factors that appear

Low ibuprofen clearance occurs in a substantial proportion of healthy subjects, is not enantiospecific, and is strongly linked to CYP2C8 and CYP2C9 polymorphisms.