Use of toxicogenomics to understand mechanisms of drug-induced hepatotoxicity during drug discovery and development

Blomme, Eric A.G.; Yang, Yi; Waring, Jeffrey F.

doi:10.1016/j.toxlet.2008.09.017

Cited by 118 publications

(87 citation statements)

References 79 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Because rifampin activates the nuclear receptor and transcription factor known as pregnane-X receptor (PXR) in human hepatocytes, it was hypothesized that A-972611 inhibits rifampin PXR activation via the CYP3A4 pathways. This hypothesis was confirmed with A-972611 inhibition of PXR, with transcriptomics revealing a novel mechanism of action for this HIV protease inhibitor [9]. More specifically, the term pharmacogenomics describes the study of variations of DNA and RNA responses to drug exposure using GWAS studies or microarray technology [6,7].…”

Section: Pharmacogenomicsmentioning

confidence: 86%

Advanced Molecular Biologic Techniques in Toxicologic Disease

et al. 2011

View full text Add to dashboard Cite

The advancement of molecular biologic techniques and their capabilities to answer questions pertaining to mechanisms of pathophysiologic events have greatly expanded over the past few years. In particular, these opportunities have provided researchers and clinicians alike the framework from with which to answer clinical questions not amenable for elucidation using previous, more antiquated methods. Utilizing extremely small molecules, namely microRNA, DNA, protein, and nanoparticles, we discuss the background and utility of these approaches to the progressive, practicing physician. Finally, we consider the application of these tools employed as future bedside point of care tests, aiding in the ultimate goal of unsurpassed patient care.

show abstract

Section: Pharmacogenomicsmentioning

confidence: 86%

Advanced Molecular Biologic Techniques in Toxicologic Disease

et al. 2011

View full text Add to dashboard Cite

show abstract

“…A number of compounds associated with IDILI but giving negative results in animal toxicology studies have been investigated with toxicogenomics technologies in animals to identify specific gene expression signatures able to predict the risk of idiosyncratic reactions in humans [42,43]. The underlying hypothesis is that changes in gene expression relevant to the pathogenic mechanism of IDILI in humans could be detected in animals despite the lack of evidence of liver injury obtained with conventional markers.…”

Section: Use Of New Biomarkers In Animal Studiesmentioning

confidence: 99%

Preventing Drug-Induced Liver Injury: How Useful Are Animal Models?

Ballet¹

2015

Dig Dis

View full text Add to dashboard Cite

Drug-induced liver injury (DILI) is the most common organ toxicity encountered in regulatory animal toxicology studies required prior to the clinical development of new drug candidates. Very few reports have evaluated the value of these studies for predicting DILI in humans. Indeed, compounds inducing liver toxicity in regulatory toxicology studies are not always correlated with a risk of DILI in humans. Conversely, compounds associated with the occurrence of DILI in phase 3 studies or after market release are often tested negative in regulatory toxicology studies. Idiosyncratic DILI is a rare event that is precipitated in an individual by the simultaneous occurrence of several critical factors. These factors may relate to the host (e.g. human leukocyte antigen polymorphism, inflammation), the drug (e.g. reactive metabolites) or the environment (e.g. diet/microbiota). This type of toxicity therefore cannot be detected in conventional animal toxicology studies. Several animal models have recently been proposed for the identification of drugs with the potential to cause idiosyncratic DILI: rats treated with lipopolysaccharide, Sod2^+/- mice, panels of inbred mouse strains or chimeric mice with humanized livers. These models are not suitable for use in the prospective screening of new drug candidates. Humans therefore constitute the best model for predicting and assessing idiopathic DILI.

show abstract

“…Indeed, several in vivo transcriptomics studies have reported the predictive character of this technology to detect hepatotoxicity [64][65][66][67][68][69] in human cell cultures of both primary hepatocytes and hepatic cell lines [64,70,71]. As mentioned before, these cell models have serious drawbacks regarding availability and functionality, respectively.…”

mentioning

confidence: 99%