Pharmacogenomics in Drug Induced Liver Injury

Andrade, Raúl J.; Agúndez, José A.G.; Lucena, M. Isabel; Martı́nez, Carmen; Cueto, Raquel; García‐Martín, Elena

doi:10.2174/138920009790711805

Cited by 68 publications

(32 citation statements)

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“…Ethnic differences in allele frequencies are a major source of variability in genetic studies related to DILI. 18 Findings obtained in populations with a low minor allele frequency, as is the case for SOD2 polymorphisms in Asian subjects, should be cautiously interpreted, because a high sample size is required to obtain enough statistical power in these populations. The role of SOD2 in drug-induced hepatotoxicity has proven contradictory.…”

Section: Discussionmentioning

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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Section: Discussionmentioning

confidence: 99%

Mitochondrial Superoxide Dismutase and Glutathione Peroxidase in Idiosyncratic Drug-Induced Liver Injury

et al. 2010

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“…Like in the case of formation of active metabolites, genetic polymorphism in addition to other factors can significantly affect the formation of reactive metabolites and protein adducts, leading to altered drug toxicity [243][244][245][246]. It can also result in differential inactivation of P450s.…”

Section: Consequence Of Bioactivation Of Drugs To Reactive Metabolitesmentioning

confidence: 99%

Bioactivation I: Bioactivation by Cytochrome P450s

Dalvie

2012

Encyclopedia of Drug Metabolism and Interactions

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Metabolism reactions generally result in detoxification of xenobiotics and are accompanied by the formation of chemically stable metabolites, which are devoid of pharmacological or toxicological activities. However, in some cases, these reactions can convert drugs to products that are either chemically reactive or pharmacologically active, a process that is commonly referred to as metabolic activation or bioactivation . Most, if not all, functionalization and conjugation reactions can result in bioactivation. Even though all enzymes have the propensity to catalyze the metabolic activation of compounds, cytochrome P450 (P450) enzymes, which generally dominate metabolism, play a major role in the metabolic activation of drugs. The primary objective of this chapter is to provide an overview of bioactivation by P450 to pharmacologically active and chemically reactive metabolites. The common reactions that result in bioactivation of xenobiotics and consequences of bioactivation have been discussed here.

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“…Metabolism-related toxicity is generally mediated by the generation of reactive metabolites from non-toxic parenteral compounds, particularly via cytochrome P450 (CYP) enzyme pathways [6]. The interindividual variability in the expression of drug metabolizing genes predisposes certain individuals to increased susceptibility to DILI [7,8]. Therefore, it is important to examine the roles of drug metabolizing enzymes and identify specific metabolizing enzymes that contribute to drug-induced liver toxicity.…”

Section: Introductionmentioning

confidence: 99%

Development of HepG2-derived cells expressing cytochrome P450s for assessing metabolism-associated drug-induced liver toxicity

Xuan

Chen

Ning

et al. 2016

Chemico-Biological Interactions

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The generation of reactive metabolites from therapeutic agents is one of the major mechanisms of drug-induced liver injury (DILI). In order to evaluate metabolism-related toxicity and improve drug efficacy and safety, we generated a battery of HepG2-derived cell lines that express 14 cytochrome P450s (CYPs) (1A1, 1A2, 1B1, 2A6, 2B6, 2C8, 2C9, 2C18, 2C19, 2D6, 2E1, 3A4, 3A5 and 3A7) individually using a lentiviral expression system. The expression/production of a specific CYP in each cell line was confirmed by an increased abundance of the CYP at both mRNA and protein levels. Moreover, the enzymatic activities of representative CYPs in the corresponding cell lines were also measured. Using our CYP-expressed HepG2 cells, the toxicity of three drugs that could induce DILI (amiodarone, chlorpromazine and primaquine) was assessed, and all of them showed altered (increased or decreased) toxicity compared to the toxicity in drugtreated wild-type HepG2 cells. CYP-mediated drug toxicity examined in our cell system is consistent with previous reports, demonstrating the potential of these cells for assessing metabolism-related drug toxicity. This cell system provides a practical in vitro approach for drug metabolism screening and for early detection of drug toxicity. It is also a surrogate enzyme source for the enzymatic characterization of a particular CYP that contributes to drug-induced liver toxicity.

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Pharmacogenomics in Drug Induced Liver Injury

Cited by 68 publications

References 0 publications

Mitochondrial Superoxide Dismutase and Glutathione Peroxidase in Idiosyncratic Drug-Induced Liver Injury

Mitochondrial Superoxide Dismutase and Glutathione Peroxidase in Idiosyncratic Drug-Induced Liver Injury

Bioactivation I: Bioactivation by Cytochrome P450s

Development of HepG2-derived cells expressing cytochrome P450s for assessing metabolism-associated drug-induced liver toxicity

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