Detection of hepatotoxicity potential with metabolite profiling (metabolomics) of rat plasma

Abstract

While conventional parameters used to detect hepatotoxicity in drug safety assessment studies are generally informative, the need remains for parameters that can detect the potential for hepatotoxicity at lower doses and/or at earlier time points. Previous work has shown that metabolite profiling (metabonomics/metabolomics) can detect signals of potential hepatotoxicity in rats treated with doxorubicin at doses that do not elicit hepatotoxicity as monitored with conventional parameters. The current study extended this observation to the question of whether such signals could be detected in rats treated with compounds that can elicit hepatotoxicity in humans (i.e., drug-induced liver injury, DILI) but have not been reported to do so in rats. Nine compounds were selected on the basis of their known DILI potential, with six other compounds chosen as negative for DILI potential. A database of rat plasma metabolite profiles, MetaMap(®)Tox (developed by metanomics GmbH and BASF SE) was used for both metabolite profiles and mode of action (MoA) metabolite signatures for a number of known toxicities. Eight of the nine compounds with DILI potential elicited metabolite profiles that matched with MoA patterns of various rat liver toxicities, including cholestasis, oxidative stress, acetaminophen-type toxicity and peroxisome proliferation. By contrast, only one of the six non-DILI compounds showed a weak match with rat liver toxicity. These results suggest that metabolite profiling may indeed have promise to detect signals of hepatotoxicity in rats treated with compounds having DILI potential.

Understanding the effect of repeated administration of meloxicam on feline renal cortex and medulla: A lipidomics and metabolomics approach

“…Lipidomics is a subset of metabolomics that involves the identification and quantification of fatty acids or their derivatives (Navas-Iglesias, Carrasco-Pancorbo, & Cuadros-Rodríguez, 2009). Metabolomics and lipidomics are powerful tools for assessing the status of cellular metabolic processes occurring in the body's tissues and have been successfully applied in the fields of human pharmacology and toxicology to unveil new mechanism(s) of drug toxicity (Boudonck et al, 2009;Clayton et al, 2006;Coen et al, 2007;Mattes et al, 2014;Rabinowitz, Purdy, Vastag, Shenk, & Koyuncu, 2011;Rivera-Velez et al, 2019;Verhoeckx et al, 2004;Wilmes et al, 2015;Yerges-Armstrong et al, 2013). Therefore, it is highly likely that assessing the effects of meloxicam in a kidney's metabolome and lipidome would reveal key metabolic changes that might lay the foundation for untangling the reason why cats are sensitive to meloxicam and possibly other NSAIDs.…”

Concurrent profiling of polar metabolites and lipids in human plasma using HILIC-FTMS

“…Blood samples are relatively easy to collect, less invasive and more stable, compared to other body fluids. Therefore, metabolite profiling of blood samples has been widely used in biomarker discovery67891011 and assessments of adverse outcome pathways (AOPs) induced by chemicals12, drugs131415 and environmental stress16. Liquid chromatography coupled with mass spectrometry (LC-MS) is one of the main techniques for blood plasma metabolite profiling171819.…”

Exploration of Biomarkers for Amoxicillin/Clavulanate‐Induced Liver Injury: Multi‐Omics Approaches

“…Pharmacometabolomic approaches have been used to identify novel DILI biomarkers . The results of a clinical trial that was performed to analyze the pharmacometabolomics patterns in urine samples from healthy subjects before and after the administration of acetaminophen indicated that N‐acetyl‐p‐benzoquinone imine may be a useful biomarker of DILI .…”