Proteomics in the search for mechanisms and biomarkers of drug-induced hepatotoxicity

Summeren, Anke Van; Renes, Johan; Delft, J.H.M. van; Kleinjans, Jos; Mariman, E.C.M.

doi:10.1016/j.tiv.2012.01.012

Cited by 47 publications

(27 citation statements)

References 76 publications

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“…However, the detection of idiosyncratic hepatotoxicants with the currently available in vitro methods remains challenging, as idiosyncratic drug reactions are unpredictable and mostly immune mediated (Van Summeren et al, 2012). The integration of data from different research platforms (proteomics, transcriptomics, metabolomics, genomics) by using a systems biology approach may provide an opportunity to identify biomarkers for the prevention of idiosyncratic DIH in clinical practice.…”

Section: Discussionmentioning

confidence: 99%

Genome-Wide Association and Replication Study of Hepatotoxicity Induced by Antiretrovirals Alone or with Concomitant Anti-Tuberculosis Drugs

Petros

Lee

Takahashi

et al. 2017

OMICS: A Journal of Integrative Biology

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Drug-induced hepatotoxicity (DIH) is a common adverse event that is associated with both antiretroviral (ARV) and anti-tuberculosis drugs (ATD). Moreover, the genetic variations predisposing ARV-and ARV-ATDinduced liver toxicity in African populations are not well investigated, despite the two diseases being the major global health problems in sub-Saharan Africa. We performed a genome-wide association study (GWAS) and replication study to identify the genetic variants linked to the risk of developing DIH due to ARV drugs alone, and ARV-ATD co-treatment in Ethiopian HIV-positive patients. Treatment-naïve newly diagnosed HIV patients (n = 719) with or without tuberculosis (TB) co-infection were enrolled prospectively and received efavirenz-based ARV therapy with or without rifampicin-based short course ATD, respectively. Whole-genome genotyping was performed by using the Illumina Omni Express Exome Bead Chip genotyping array with 951,117 single nucleotide polymorphisms (SNPs) on a total of 41 cases of DIH, and 452 people without DIH (treatment tolerants). The replication study was carried out for 100 SNPs with the lowest p-values (top SNPs) by using an independent cohort consisting of 18 DIH cases and 208 treatment tolerants. We identified a missense SNP rs199650082 (2756G/A, R919Q, p = 1.4 · 10 -6 , odds ratio [OR] = 18.2, 95% confidence interval [CI] = 7.1-46.9) in an endoplasmic reticulum to the nucleus signaling-1 (ERN1) gene on chromosome 17 to be associated with DIH in the ARV-only cohort. In the ARV-ATD co-treatment groups, rs4842407, a long intergenic noncoding RNAs (lincRNAs) transcript variant on chromosome 12, was associated with DIH ( p = 5.3 · 10 -7, OR = 5.4, 95% CI = 2.8-10.3). These genetic variants that are putatively associated with DIH due to ARV drugs alone and ARV-ATD co-treatment establish a foundation for future personalized medicine in people with HIV and TB and call for larger studies in independent populations.

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Section: Discussionmentioning

confidence: 99%

Genome-Wide Association and Replication Study of Hepatotoxicity Induced by Antiretrovirals Alone or with Concomitant Anti-Tuberculosis Drugs

Petros

Lee

Takahashi

et al. 2017

OMICS: A Journal of Integrative Biology

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“…Activity-based chemical proteomics is a powerful tool to identify new drug targets and define the specificity of drug action in complex biological matrices (22)(23)(24)(25)(26). Under this approach, a chemical probe is designed to react with enzymes of a specific class irrespective of their substrate specificities.…”

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confidence: 99%

Chemoproteomic Analysis of Intertissue and Interspecies Isoform Diversity of AMP-activated Protein Kinase (AMPK)

Puppala

Feng

et al. 2013

Journal of Biological Chemistry

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Background: AMPK is a heterotrimeric enzyme targeted for drug discovery (activation) in diabetes. Results: Diversity of AMPK was studied by chemical capture and proteomic LC-MS. Conclusion: AMPK of human and rat livers differs with respect to the ␤ chain. Certain direct activators only activate AMPK containing the ␤1 form. Significance: Interspecies divergence could compromise the translatability of preclinical data.

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“…Thus far, toxicoproteomic attempts to predict DILI have demonstrated limited efficacy when performed in vitro [75]. Toxicoproteomics performed on in vitro cultures have the key advantage that biologically significant alterations can be monitored without relying on whole animals [76].…”

Section: Profiling Technologiesmentioning

confidence: 99%

“…Exposing HepG2 cells to three model hepatotoxins that are known to cause necrotic, steatotic or cholestatic liver injury, researchers were only able to distinguish cholestatic injury from untreated controls [75]. The study failed to successfully discern necrotic and steatotic events, however, the ability to detect adverse cholestatic events in HepG2 cells is noteworthy, as these cells are not known to form biliary structures in a monolayer but rather present as parenchymal cells [43].…”

Section: Profiling Technologiesmentioning

confidence: 99%

Pre-Clinical Assessment of the Potential Intrinsic Hepatotoxicity of Candidate Drugs

Tonder¹,

Steenkamp²,

Gulumian³

2013

New Insights Into Toxicity and Drug Testing

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Proteomics in the search for mechanisms and biomarkers of drug-induced hepatotoxicity

Cited by 47 publications

References 76 publications

Genome-Wide Association and Replication Study of Hepatotoxicity Induced by Antiretrovirals Alone or with Concomitant Anti-Tuberculosis Drugs

Genome-Wide Association and Replication Study of Hepatotoxicity Induced by Antiretrovirals Alone or with Concomitant Anti-Tuberculosis Drugs

Chemoproteomic Analysis of Intertissue and Interspecies Isoform Diversity of AMP-activated Protein Kinase (AMPK)

Pre-Clinical Assessment of the Potential Intrinsic Hepatotoxicity of Candidate Drugs

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