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Title: The hepatic adaptive response to repeat acetaminophen exposure
Author: Eakins, R. M.
ISNI:       0000 0004 6058 9742
Awarding Body: University of Liverpool
Current Institution: University of Liverpool
Date of Award: 2016
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The adaptive response to chemical stress arises when an injurious exposure to a drug initiates phenotypic changes in the liver. These phenotypic changes limit hepatotoxicity upon subsequent exposures, and constitute an important evolutionary safeguard to the individual's survival. The factors governing hepatic adaptation to the popular analgesic and antipyretic acetaminophen (paracetamol) represent valuable research avenues, since acetaminophen toxicity is a leading cause of emergency hospital admissions through accidental and intentional overdose. Knowledge of the broader mechanisms governing hepatic adaptation to chemical exposure are limited; and concerning acetaminophen specifically, the research focus to date has been on select proteins implicated in metabolism. The aim of this thesis was to investigate the molecular mechanisms of adaptation to chemical stress in two preclinical models using the classical hepatotoxin acetaminophen. These models have been characterised through clinically accepted toxicological and histopathological assessments, establishing acetaminophen-induced injury in high dose acetaminophen exposure groups in both rat and mouse models. A global proteomic analysis of rat liver has given insight into the changes in abundance of a subset of proteins common to all rats throughout the duration of the repeat exposure study, demonstrating that the process of adaptation to repeat acetaminophen exposure is not mediated by a single enzyme or pathway, but rather by a dynamic shift in expression of a large number of hepatic proteins. Key observations included widespread loss of phase I, II and III drug metabolising enzymes at the peak of toxicity, indicating a phenotypic shift away from drug metabolism. Focusing on the role of cytochrome P450 2E1 (CYP2E1) as the major bioactivator of acetaminophen revealed changes in both expression and activity of this enzyme as the timecourse progressed. Whilst initial similarities were seen in terms of hepatocellular injury, comparison of key markers of the adaptive response in rat and mouse revealed that the regenerative response provoked in this model is incompletely conserved. The rat showed induction of Nrf2-dependent proteins implicated in redox homeostasis, as well as extensive mitotic activity, restoring both mass and function to the liver despite continued dosing. The mouse was still able to adapt despite an absence of Nrf2 activation and no significant mitosis, indicating that the mechanisms by which each organism survives is quite different. The findings of this work have implications for research into drug development and preclinical modelling of toxicity and adaptation, since the pharmaceutical industry typically employs rats and academia uses mice; however neither is a complete analogue of the human response. Additionally, further characterisation of the influence which adaptation has on the metabolic fate of subsequent xenobiotic exposures will be of value to the drug development and clinical management pathways. Further into the future, an improved understanding of the constituents of human adaptation, and the consequences of its failure, may permit more effective management of both acute and chronic liver injury.
Supervisor: Goldring, C. E. P. ; Kitteringham, N. ; Park, B. K. Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral