Cunningham, Katharine, Claus, Sandrine P., Lindon, John C., Holmes, Elaine, Everett, Jeremy ORCID: 0000-0003-1550-4482 , Nicholson, Jeremy K. and Coen, Muireann (2012) Pharmacometabonomic characterization of xenobiotic and endogenous metabolic phenotypes that account for inter-individual variation in isoniazid-induced toxicological response. Journal of Proteome Research, 11 (9). pp. 4630-4642. ISSN 1535-3893 (Print), 1535-3907 (Online) (doi:https://doi.org/10.1021/pr300430u)

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Abstract

An NMR-based pharmacometabonomic approach was applied to investigate inter-animal variation in response to isoniazid (INH; 200 and 400 mg/kg) in male Sprague−Dawley rats, alongside complementary clinical chemistry and histopathological analysis. Marked inter-animal variability in central nervous system (CNS) toxicity was identified following administration of a high dose of INH, which enabled characterization of CNS responders and CNS non-responders. High-resolution post-dose urinary 1H NMR Spectra were modeled both by their xenobiotic and endogenous metabolic information sets, enabling simultaneous identification of the differential metabolic fate of INH and its associated endogenous metabolic consequences in CNS responders and CNS non-responders. A characteristic xenobiotic metabolic profile was observed for CNS responders, which revealed higher urinary levels of pyruvate isonicotinylhydrazone and β-glucosyl isonicotinylhydrazide and lower levels of acetylisonia id compared to CNS non-responders. This suggested that the capacity for acetylation of INH was lower in CNS responders, leading to increased metabolism via conjugation with pyruvate and glucose. In addition, the endogenous metabolic profile of CNS responders revealed higher urinary levels of lactate and glucose, in comparison to CNS non-responders. Pharmacometabonomic analysis of the pre-dose 1H NMR urinary spectra identified a metabolic signature that correlated with the development of INH-induced adverse CNS effects and may represent a means of predicting adverse events and acetylation capacity when challenged with high dose INH. Given the widespread use of INH for the treatment of tuberculosis, this pharmacometabonomic screening approach may have translational potential for patient stratification to minimize adverse events.

Item Type:	Article
Additional Information:	[1] Publication Date (Web): August 9, 2012. [2] Published in print: September 7, 2012 [3] Published as: Journal of Proteome Research, 2012, 11 (9), pp 4630–4642. [4] This work was funded by a BBSRC CASE studentship in collaboration with Pfizer. The MRC Integrative Toxicology Training Partnership (ITTP) is acknowledged for financial support to M.C. We thank Dr Claude Charuel and the technical staff of Pfizer Global R&D in Amboise, France, for their assistance in performing the animal-related work. We thank Dr. O. Cloarec for assistance with validation of statistical models and Dr. T. A. Clayton for valuable contributions to the study design and for assistance in data analysis and interpretation.
Uncontrolled Keywords:	metabonomics, pharmacometabonomics, NMR spectroscopy
Subjects:	R Medicine > RS Pharmacy and materia medica
Faculty / School / Research Centre / Research Group:	Faculty of Engineering & Science > School of Science (SCI) Faculty of Engineering & Science
Related URLs:	Publisher Organisation
Last Modified:	19 Nov 2024 14:05
URI:	http://gala.gre.ac.uk/id/eprint/8969

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