Genetic polymorphisms of manganese superoxide dismutase, NAD(P)H:quinone oxidoreductase, glutathione S-transferase M1 and T1, and the susceptibility to drug-induced liver injury

Huang, Yo-Ping; Su, Wei‐Juin; Huang, Yi-Hsiang; Chen, Chih-Yen; Chang, Full‐Young; Lin, Han‐Chieh; Lee, Shou‐Dong

doi:10.1016/j.jhep.2007.02.009

Cited by 193 publications

(174 citation statements)

References 42 publications

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“…Namely, glutathione-S-transferases (GSTs) have a pivotal role as antioxidant defense mechanisms, and in conjunction with SULT and CYP2E1, products act by inactivating xenobiotics and products of oxidative stress (Bolt and Thier 2006). Moreover, GSTM 1 and GSTT1 null genotypes are associated with type 2 diabetes and its complications which (Doney et al 2005) are closely related to NAFLD with several reports underlining the role of GSTT on liver damage (Targher et al 2010;Huang et al 2007;Ueda et al 2007;Oniki et al 2007). No one study so far ever addressed the effect of SULT1A1 and CYP1A1 polymorphisms on NAFLD, while GSTT1 but not GSTT1 genetic polymorphisms have been associated with NAFLD in a sample of the Iranian population (Hashemi et al 2012).…”

Section: Discussionmentioning

confidence: 99%

A case–control study on the effect of metabolic gene polymorphisms, nutrition, and their interaction on the risk of non-alcoholic fatty liver disease

et al. 2014

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The oxidative stress is a key issue in the etiology of non-alcoholic fatty liver disease (NAFLD). The aim of our study was to evaluate the effect of metabolic gene polymorphisms involved in the oxidative stress (GSTT1, GSTM1, SULT1A1, CYP2E1, and 1A1), lifestyle and nutrition aspects, and their interaction, on the risk of NAFLD. We enrolled 294 cases and 359 controls, and collected demographics, anthropometric, lifestyle, and nutrition data. A subgroup of NAFLD provided additional data on nutrients and on physical activity engagement. Each patient provided a blood sample for DNA extraction and genotyping. Clinical and laboratory data were collected from cases. Multivariable analysis shows a significant protective effect of age, gender, and moderate drinking habits on the risk of NAFLD, while an increased risk for greater consumption of fruit and grilled meat or fish. Significant interactions were reported between alcohol consumption, fruit intake, grilled meat and fish, and selected genetic variants. From the subgroup analysis, a moderate/high consumption of fat and/or grilled meat/fish, and a high consumption of white meat increase the risk of NAFLD. Engaging any physical activity at least 1 time/ week halves the risk of NAFLD. Besides confirming the beneficial effect of moderate alcohol intake and regular physical activity, and the increased risk associated with high fruit and fat intake, for the first time, we report a detrimental effect of grilled food on NAFLD risk. An effect modification by selected gene variants increases the risk in combination with fruit and grilled food intake.

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Section: Discussionmentioning

confidence: 99%

A case–control study on the effect of metabolic gene polymorphisms, nutrition, and their interaction on the risk of non-alcoholic fatty liver disease

et al. 2014

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“…15 Genotyping of the SOD2 Val16Ala polymorphism (rs4880) was performed as previously described by Huang and co-workers. 5 In brief, a 172-bp fragment containing the C47T base exchange was amplified using primers 5 0 -CAG CCC AGC CTG CGT AGA CGG-3 0 and 5 0 -GCG TTG ATG TGA GGT TCC AG-3 0 . Amplification was performed with 40 cycles of 92 C for 1 minute, 59 C for 1 minute, and 72 C for 1 minute in a total volume of 25 lL.…”

Section: Methodsmentioning

confidence: 99%

“…5 This unexpected finding has been attributed to the accumulation of higher amounts of hydrogen peroxide generated by the enhanced SOD2 activity.…”

Section: Because Environmentalmentioning

confidence: 99%

Mitochondrial superoxide dismutase and glutathione peroxidase in idiosyncratic drug-induced liver injury

et al. 2010

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Drug-induced liver injury (DILI) susceptibility has a potential genetic basis. We have evaluated possible associations between the risk of developing DILI and common genetic variants of the manganese superoxide dismutase (SOD2 Val16Ala) and glutathione peroxidase (GPX1 Pro200Leu) genes, which are involved in mitochondrial oxidative stress management. Genomic DNA from 185 DILI patients assessed by the Council for International Organizations of Medical Science scale and 270 sex-and age-matched controls were analyzed. The SOD2 and GPX1 genotyping was performed using polymerase chain reaction restriction fragment length polymorphism and TaqMan probed quantitative polymerase chain reaction, respectively. The statistical power to detect the effect of variant alleles with the observed odds ratio (OR) was 98.2% and 99.7% for bilateral association of SOD2 and GPX1, respectively. The SOD2 Ala/Ala genotype was associated with cholestatic/mixed damage (OR 5 2.3; 95% confidence interval [CI] 5 1.4-3.8; corrected P [Pc] 5 0.0058), whereas the GPX1 Leu/Leu genotype was associated with cholestatic injury (OR 5 5.1; 95%CI 5 1.6-16.0; Pc 5 0.0112). The presence of two or more combined risk alleles (SOD2 Ala and GPX1 Leu) was more frequent in DILI patients (OR 5 2.1; 95%CI 5 1.4-3.0; Pc 5 0.0006). Patients with cholestatic/mixed injury induced by mitochondria hazardous drugs were more prone to have the SOD2 Ala/Ala genotype (OR 5 3.6; 95%CI 5 1.4-9.3; Pc 5 0.02). This genotype was also more frequent in cholestatic/mixed DILI induced by pharmaceuticals producing quinone-like or epoxide metabolites (OR 5 3.0; 95%CI 5 1.7-5.5; Pc 5 0.0008) and S-oxides, diazines, nitroanion radicals, or iminium ions (OR 5 16.0; 95%CI 5 1.8-146.1; Pc 5 0.009). Conclusion: Patients homozygous for the SOD2 Ala allele and the GPX1 Leu allele are at higher risk of developing cholestatic DILI. SOD2 Ala homozygotes may be more prone to suffer DILI from drugs that are mitochondria hazardous or produce reactive intermediates. (HEPATOLOGY 2010;52:303-312)

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“…Most of these investigations have been performed in Asian patients exposed to antituberculosis drugs; it is known that GST enzymes play an important role in isoniazid metabolism. [5][6][7] Lucena et al included patients with DILI in whom the main causative therapeutic group of drugs were anti-infectives, especially amoxicillin-clavulanic acid. Among the group who received anti-infective drugs, only five patients were receiving antituberculosis drugs, which were not specified by the authors.…”

Section: To the Editormentioning

confidence: 99%

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

et al. 2009

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We read with interest the work of Lucena et al. about genetic susceptibility to drug-induced liver injury (DILI). 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. [2][3][4] However, in many cases, the drug-metabolism pathways and the exact mechanism and factors contributing to liver toxicity remain poorly understood. From pharmacological studies, there are data showing that GST genotypes may be linked to DILI secondary to hepatocellular damage mechanisms based on the participation of GST enzymes in drug metabolism. 4 Thus, studying drugs in which the DILI mechanism is unknown or secondary to a hypersensitive reaction could be confusing. Most of these investigations have been performed in Asian patients exposed to antituberculosis drugs; it is known that GST enzymes play an important role in isoniazid metabolism. 5-7 Lucena et al. included patients with DILI in whom the main causative therapeutic group of drugs were anti-infectives, especially amoxicillin-clavulanic acid. Among the group who received anti-infective drugs, only five patients were receiving antituberculosis drugs, which were not specified by the authors. Among these five patients, four showed one of these null polymorphisms (GSTM1 or GSTT1) and one had a normal genotype, but the authors did not specify the combination of the null alleles or in which genes.The absence of this data is general for all types of drugs studied; there is no information about what gene was predominantly deleted for each drug. Again, focusing on the antituberculosis drug group, it is not surprising there was no association between the presence of GSTM1 and GSTT1-null mutations and the risk of DILI due to the small number of patients in this subgroup. Our group performed the first study with 95 Caucasian patients originally from Spain to investigate the influence of these null polymorphisms on the risk of antituberculosis drug-induced hepatotoxicity and showed an enhanced risk of DILI in GSTT1-null carriers (odds ratio ϭ 2.6; P ϭ 0.03). 8 The frequency of double GSTM1 and GSTT1 genotype carriers was higher in cases than in controls; however, these differences did not reach significance because the power of the associations related to the small size of the patient subgroup. 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 signific...

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Genetic polymorphisms of manganese superoxide dismutase, NAD(P)H:quinone oxidoreductase, glutathione S-transferase M1 and T1, and the susceptibility to drug-induced liver injury

Cited by 193 publications

References 42 publications

A case–control study on the effect of metabolic gene polymorphisms, nutrition, and their interaction on the risk of non-alcoholic fatty liver disease

A case–control study on the effect of metabolic gene polymorphisms, nutrition, and their interaction on the risk of non-alcoholic fatty liver disease

Mitochondrial superoxide dismutase and glutathione peroxidase in idiosyncratic drug-induced liver injury

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

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