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Adaptation to acetaminophen exposure elicits major changes in expression and distribution of the hepatic proteome.

Eakins, R and Walsh, J and Randle, L and Jenkins, RE and Schuppe-Koistinen, I and Rowe, C and Starkey Lewis, P and Vasieva, O and Prats, N and Brillant, N and Auli, M and Bayliss, M and Webb, S and Rees, JA and Kitteringham, NR and Goldring, CE and Park, BK (2015) Adaptation to acetaminophen exposure elicits major changes in expression and distribution of the hepatic proteome. Scientific Reports, 5. ISSN 2045-2322

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Abstract

Acetaminophen overdose is the leading cause of acute liver failure. One dose of 10-15 g causes severe liver damage in humans, whereas repeated exposure to acetaminophen in humans and animal models results in autoprotection. Insight of this process is limited to select proteins implicated in acetaminophen toxicity and cellular defence. Here we investigate hepatic adaptation to acetaminophen toxicity from a whole proteome perspective, using quantitative mass spectrometry. In a rat model, we show the response to acetaminophen involves the expression of 30% of all proteins detected in the liver. Genetic ablation of a master regulator of cellular defence, NFE2L2, has little effect, suggesting redundancy in the regulation of adaptation. We show that adaptation to acetaminophen has a spatial component, involving a shift in regionalisation of CYP2E1, which may prevent toxicity thresholds being reached. These data reveal unexpected complexity and dynamic behaviour in the biological response to drug-induced liver injury.

Item Type: Article
Subjects: R Medicine > RM Therapeutics. Pharmacology
Divisions: Pharmacy & Biomolecular Sciences
Publisher: NATURE PUBLISHING GROUP
Related URLs:
Date Deposited: 30 Nov 2015 13:22
Last Modified: 30 Nov 2015 13:22
DOI or Identification number: 10.1038/srep16423
URI: http://researchonline.ljmu.ac.uk/id/eprint/2404

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