Genetic and Molecular Factors in Drug-Induced Liver Injury: A Review

Pachkoria, Ketevan; Lucena, M. Isabel; Molokhia, Mariam; Cueto, Raquel; Carballo, A; Carvajal, Alfonso; Andrade, Raúl J.

doi:10.2174/157488607780598287

Cited by 28 publications

(14 citation statements)

References 181 publications

(196 reference statements)

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“…Other studies have examined the role of CYP-2C9 and CYP-2C19 polymorphisms for associations with druginduced idiosyncratic reactions (Pachkoria et al 2007). While arguably liver reactions from NSAIDs may be associated with abnormalities of phase 1 and phase 2 metabolism, the studies by Pachkoria et al (2007) have failed to establish if polymorphisms of CYP-2C9 or CYP-2C19 are associated with liver disease.…”

Section: Pharmacokinetics In Adultsmentioning

confidence: 99%

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Ibuprofen: pharmacology, efficacy and safety

2009

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This assessment of the safety and benefits of ibuprofen can be summarized thus: (1) Ibuprofen at OTC doses has low possibilities of serious GI events, and little prospect of developing renal and associated CV events. Ibuprofen OTC does not represent a risk for developing liver injury especially the irreversible liver damage observed with paracetamol and the occasional liver reactions from aspirin. (2) The pharmacokinetic properties of ibuprofen, especially the short plasma half-life of elimination, lack of development of pathologically related metabolites (e.g. covalent modification of liver proteins by the quinine-imine metabolite of paracetamol or irreversible acetylation of biomolecules by aspirin) are support for the view that these pharmacokinetic and notably metabolic effects of ibuprofen favour its low toxic potential. (3) The multiple actions of ibuprofen in controlling inflammation combine with moderate inhibition of COX-1 and COX-2 and low residence time of the drug in the body may account for the low GI, CV and renal risks from ibuprofen, especially at OTC doses.

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Section: Pharmacokinetics In Adultsmentioning

confidence: 99%

“…While arguably liver reactions from NSAIDs may be associated with abnormalities of phase 1 and phase 2 metabolism, the studies by Pachkoria et al (2007) have failed to establish if polymorphisms of CYP-2C9 or CYP-2C19 are associated with liver disease.…”

Section: Pharmacokinetics In Adultsmentioning

confidence: 99%

Ibuprofen: pharmacology, efficacy and safety

2009

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“…The causes for DILI are manifold and include both drug-related properties and characteristics of individual patients, which include genotype, underlying disease, comedications, and various other demographic factors (Pachkoria et al, 2007). Human hepatocytes have clear potential value in toxicity evaluations, because they express a broad range of metabolizing enzymes and other desirable differentiated functions (McGinnity et al, 2004;Hewitt et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

Characterization of THLE-Cytochrome P450 (P450) Cell Lines: Gene Expression Background and Relationship to P450-Enzyme Activity

Soltanpour

Hilgendorf²,

Ahlström³

et al. 2012

Drug Metabolism and Disposition

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ABSTRACT:The hepatic SV40 large T-antigen immortalized human liver epithelial (THLE) cell line and sublines transfected with cytochromes P450 (P450s) are increasingly being used for evaluation of potential drug-induced liver injury. So far, the available information on transporter and enzyme expression in these transfected cell systems is scattered. The purpose of this study was to characterize THLE cell lines with respect to transporter and enzyme expression. The mRNA expression of 96 typical drug absorption, distribution, metabolism and excretion genes, which encode a selection of transporters, phase I and II drugmetabolizing enzymes, and nuclear hormone receptors, was investigated in five THLE cell lines transfected with individual human P450s and in mock-transfected THLE-null cells using real-time polymerase chain reaction. The majority of the analyzed genes was either absent or expressed at low levels in the THLE-null and THLE-P450 cells, apart from housekeeping genes and the individual transfected P450s. Enzyme activity measurements provided confirmatory functional data for CYP2C9 and CYP3A4. Comparison with gene expression in human liver revealed an overall much lower gene expression in the THLE cell lines. The low levels of expression of a broad range of P450 genes in the THLE cell lines highlight the value of studies undertaken with P450-expressing cell lines for investigation of mechanisms of P450 metabolite-mediated hepatotoxicity. However, when attempting to translate between data obtained in THLE cell lines in vitro and functional consequences in vivo, it is important to take account of their limited expression of genes encoding many other drug-metabolizing enzymes and hepatic transporters. IntroductionDrug-induced liver injury (DILI) is a leading cause of clinically significant adverse drug reactions (which include fatal liver failure), withdrawal of licensed drugs, failure to register new drugs, and compound termination due to toxicity during drug development (Kaplowitz, 2005). The causes for DILI are manifold and include both drug-related properties and characteristics of individual patients, which include genotype, underlying disease, comedications, and various other demographic factors (Pachkoria et al., 2007). Human hepatocytes have clear potential value in toxicity evaluations, because they express a broad range of metabolizing enzymes and other desirable differentiated functions (McGinnity et al., 2004;Hewitt et al., 2007). However, because use of hepatocytes to support assessment of toxicity during drug discovery is limited by their relatively high cost and restricted availability, alternative model systems are needed (Kalgutkar and Soglia, 2005). One promising model is the THLE-P450 cell lines, which were developed by transfection of SV40 large T-antigen immortalized human liver epithelial cells with individual human cytochrome P450 (P450) isoforms CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 (Pfeifer et al., 1993). The panel of THLE cell lines have been used to explore involvement of indiv...

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“…There are two main reasons for this: firstly genetic factors partially account for individual susceptibility to DILI [52]. Secondly, unique gene-expression profiles are expected to be associated with drugs with similar DILI potential, or similar mechanisms, therefore they could be used as biomarkers [37].…”

Section: Biomarkers Of Dilimentioning

confidence: 99%

In silicomodels for drug-induced liver injury – current status

Przybylak

Cronin

2012

Expert Opinion on Drug Metabolism & Toxicology

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Most of the predictive methods discussed in this review are based on the structural properties of chemicals and do not take into account genetic and environmental factors; therefore, their predictions are still uncertain. To improve the predictability of in silico models for DILI, it is essential to better understand its mechanisms as well as to develop sensitive toxicogenomics biomarkers, which show relatively good differentiation between hepatotoxins and non-hepatotoxins.

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Genetic and Molecular Factors in Drug-Induced Liver Injury: A Review

Cited by 28 publications

References 181 publications

Ibuprofen: pharmacology, efficacy and safety

Ibuprofen: pharmacology, efficacy and safety

Characterization of THLE-Cytochrome P450 (P450) Cell Lines: Gene Expression Background and Relationship to P450-Enzyme Activity

In silicomodels for drug-induced liver injury – current status

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