Risk identification and management: MRI as a research tool in toxicology studies of new chemical entities

Tengowski, Mark W.; Kotyk, John J.

doi:10.1007/3-7643-7426-8_7

Cited by 7 publications

(7 citation statements)

References 67 publications

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“…Drug-induced hepatotoxicity reduces the rate of approval of new chemical entities and plays a major role in the withdrawal of approved drugs from the market 3,5–7 . We have shown that our nanoparticle is capable of simultaneous and differential dual-analyte sensing using two optical channels inherently free from cross-talk, enabling in vivo and longitudinal detection of drug-induced hepatic oxidative and nitrosative stress.…”

Section: Discussionmentioning

confidence: 99%

“…Drug-induced hepatotoxicity is also the single most important cause of both United States Food and Drug Administration (FDA) non-approval and withdrawal from the market after approval. Reducing hepatotoxicity during drug development may be possible with innovative pre-clinical hepatotoxicity screening methods 3,5–7 . Pre-clinical interrogation of drug hepatotoxicity may also have added benefits in improving patient safety and therapeutic outcomes 6,8 .…”

mentioning

confidence: 99%

“…protein, glutathione) 4,10 . However, electrophiles are a poor predictor of the hepatotoxic potential of the parent drug molecule 4 , and do not represent a mechanistic link between the administered drug and toxic outcome 7,10,11,13 .…”

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confidence: 99%

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Real-time imaging of oxidative and nitrosative stress in the liver of live animals for drug-toxicity testing

et al. 2014

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Current drug-safety assays for hepatotoxicity rely on biomarkers with low predictive power. The production of radical species, specifically reactive oxygen species (ROS) and reactive nitrogen species (RNS), has been proposed as an early unifying event linking the bioactivation of drugs to hepatotoxicity and as a more direct and mechanistic indicator of hepatotoxic potential. Here we present a nanosensor for rapid, real-time in vivo imaging of drug-induced ROS and RNS for direct evaluation of acute hepatotoxicity. By combining fluorescence resonance energy transfer (FRET) and chemiluminescence resonance energy transfer (CRET), our semiconducting polymer–based nanosensor simultaneously and differentially detects RNS and ROS using two optically independent channels. Drug-induced hepatotoxicity and its remediation are imaged longitudinally in mice following systemic challenge with acetaminophen or isoniazid. Dose-dependent ROS and RNS activity is detected in the liver within minutes of drug challenge, preceding histological changes, protein nitration and DNA double strand break induction.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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Real-time imaging of oxidative and nitrosative stress in the liver of live animals for drug-toxicity testing

et al. 2014

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“…Hence, this phenomenon also widely affects the pharmaceutical industry, leading to drug withdrawal even after release into the market . Innovative preclinical hepatotoxicity screening methods could help examine hepatotoxicity during drug development; however, the development proved to be complicated because many biomarkers exist during the DILI process. − The lack of a straightforward preclinical screening assay is also an issue.…”

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confidence: 99%

Investigation of Drug-Induced Hepatotoxicity and Its Remediation Pathway with Reaction-Based Fluorescent Probes

et al. 2017

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Drug-induced liver injury (DILI) is considered a serious problem related to public health, due to its unpredictability and acute response. The level of peroxynitrite (ONOO) generated in liver has long been regarded as a biomarker for the prediction and measurement of DILI. Herein we present two reaction-based fluorescent probes (Naph-ONOO and Rhod-ONOO) for ONOO through a novel and universally applicable mechanism: ONOO-mediated deprotection of α-keto caged fluorophores. Among them, Rhod-ONOO can selectively accumulate and react in mitochondria, one of the main sources of ONOO, with a substantial lower nanomolar sensitivity of 43 nM. The superior selectivity and sensitivity of two probes enable real-time imaging of peroxynitrite generation in lipopolysaccharide-stimulated live cells, with a remarkable difference from cells doped with other interfering reactive oxygen species, in either one- or two-photon imaging modes. More importantly, we elucidated the drug-induced hepatotoxicity pathway with Rhod-ONOO and revealed that CYP450/CYP2E1-mediated enzymatic metabolism of acetaminophen leads to ONOO generation in liver cells. This is the first time to showcase the drug-induced hepatotoxicity pathways by use of a small-molecule fluorescent probe. We hence conclude that fluorescent probes can engender a deeper understanding of reactive species and their pathological revelations. The reaction-based fluorescent probes will be a potentially useful chemical tool to assay drug-induced hepatotoxicity.

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“…For example, animal MRI has been demonstrated to be a useful tool to measure hepatic steatosis, quantify liver fat/water ratios, rat brain lesion, and noninvasively monitor for possible compound-induced toxicity, etc. (Weiss et al, 1994; Schmitz et al, 1996; Hockings et al, 2003; Preece et al, 2004; Zhang et al, 2004; Tengowski and Kotyk, 2005).…”

Section: In Vivo Preclinical Imagingmentioning

confidence: 99%

Modern Imaging Technologies in Toxicologic Pathology: An Overview

Ying

Monticello

2006

Toxicol Pathol

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Modern imaging technology, now utilized in most biomedical research areas (bioimaging), enables the detection and visualization of biological processes at various levels of the molecule, organelle, cell, tissue, organ and/or whole body. In toxicologic pathology, the impact of modern imaging technology is becoming apparent from digital histopathology to novel molecular imaging for in vivo studies. This overview summarizes recent progresses in digital microscopy imaging and newly developed digital slide techniques. Applications of virtual microscopy imaging are discussed and compared to traditional optical microscopy reading. New generation digital pathology approaches, including automatic slide inspection, digital slide databases and image management are briefly introduced. Commonly used in vivo preclinical imaging technologies are also summarized. While most of these new imaging techniques are still undergoing rapid development, it is important that toxicologic pathologists embrace and utilize these technologies as advances occur.

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Risk identification and management: MRI as a research tool in toxicology studies of new chemical entities

Cited by 7 publications

References 67 publications

Real-time imaging of oxidative and nitrosative stress in the liver of live animals for drug-toxicity testing

Real-time imaging of oxidative and nitrosative stress in the liver of live animals for drug-toxicity testing

Investigation of Drug-Induced Hepatotoxicity and Its Remediation Pathway with Reaction-Based Fluorescent Probes

Modern Imaging Technologies in Toxicologic Pathology: An Overview

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