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

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

Hepatotoxicity in 2011: advancing resolutely

“…Estrogen-induced cholestasis is associated with mutations in gene ABC B11, which codes for the bile salt export pump (17), and valproate-related liver toxicity is linked to mutations in the gene encoding mitochondrial DNA polymerase gamma, POL G1 (18). On the other hand, a double null genotype for cytosolic glutathione transferase (GST M1 T1) -a key enzyme in the defense against oxidative stress-entails an increased risk for liver toxicity with various drugs, particularly nonsteroidal anti-inflammatory drugs and antibacterials (19). No single risk factor to date has proven sufficiently predictive of hepatotoxicity in a given individual.…”

Glutathione S-transferase M1 and T1 null genotypes increase susceptibility to drug-induced liver injury #

“…The study by Lucena et al corroborated this observation. 1 We also observed a possible association between the risk of severe hepatotoxicity and the presence of the GSTT1-null polymorphism among six patients with severe hepatotoxicity; five (83.3%) presented with the GSTT1-null polymorphism (P ϭ 0.08). Moreover, the maximum peak of alanine aminotransferase was higher among patients with the GSTT1-null polymorphism {342 IU/L [Interquartile Range (IQR) 167-755] versus 216 IU/L [IQR 150-271]}, although without significance (P ϭ 0.07; unpublished data).…”

“…1 There is an interest in studying the possible relationship between glutathione S-transferase (GST) at the M1 and T1 loci and the risk of hepatotoxicity secondary to drugs. The study of these genetic polymorphisms should be considered a target in the investigation of drugrelated hepatotoxicity mediated by metabolic idiosyncratic mechanisms.…”

Гематологічний Профіль У Щурів При Експериментальному Диклофенак-Індукованому Гепатиті

“…Тому специфічним проявом диклофенак-індукованого ураження печінки поряд із збереженістю дольової структури органу є дифузний некроз гепатоцитів із моноцитарною та еозинофільною інфільтрацією. Крім того, за токсичного ураження печінки натрію диклофенаком у мітохондріальній і ендоплазматичній мембранах гепатоцитів зростає вміст загального і вільного холестеролу та знижується -фосфоліпідів, що вказує на інтенсифікацію пероксидного окиснення ліпідів (Tomov and Velichkova-Markova, 1983;Lucena et al, 2008;Calderon et al, 2010). При цьому порушується детоксикаційна, протеїнсинтезувальна функції печінки, пошкоджуються клітинні та субклітинні мембрани, що також призводить до руйнування цілісності клітин печінки (Gariani et al, 2017).…”