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Utility of the HRN™ (hepatic cyp reductase null) mice for investigating mechanisms of liver toxicity of carboxylic-acid-containing drugs

Akingbasote, James Adebola (2012)
M.Res. thesis, University of Birmingham.

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Abstract

Many carboxylic-acid-containing drugs cause liver injury in humans. Examples include fenclozic acid (FA), which was withdrawn due to jaundice observed in clinical trials, and diclofenac (DFC) which remains widely prescribed despite being associated with liver damage. To explore whether these toxicities could be due to metabolic bioactivation mediated by cytochrome P450 (CYP) or conjugative enzymes, covalent binding (CVB) assays were done using liver microsomal incubations from wild-type and hepatic cytochrome P450 reductase null (HRN™) mice, which are deficient in CYP activity. High levels of CYP-mediated CVB of [14C]-FA and [14C]-DFC were observed in wild-type microsomes, but not in HRN™ microsomes. No UDPGAmediated CVB was detected in microsomes incubated with [14C]-FA. Wild-type and HRN™ mice were orally administered DFC or FA orally for 7days. At 100 mg/kg, FA caused a significant (p<0.05) time-dependent increase in plasma alanine amino transferase (ALT) in wild-type but not HRN™ mice. Aberrant liver histopathology and liver clinical chemistry were evident in HRNTM mice and treatment with DFC and FA “normalised” the elevated ALT levels. These data demonstrate that FA undergoes CYP mediated bioactivation and that HRNTM mice are well suited to investigations of metabolism, but not of liver toxicity, due to impaired liver function.

Type of Work:M.Res. thesis.
Supervisor(s):Kenna, Gerry
School/Faculty:Colleges (2008 onwards) > College of Life & Environmental Sciences
Department:School of Biosciences
Subjects:RA Public aspects of medicine
RC Internal medicine
Institution:University of Birmingham
ID Code:3717
This unpublished thesis/dissertation is copyright of the author and/or third parties. The intellectual property rights of the author or third parties in respect of this work are as defined by The Copyright Designs and Patents Act 1988 or as modified by any successor legislation. Any use made of information contained in this thesis/dissertation must be in accordance with that legislation and must be properly acknowledged. Further distribution or reproduction in any format is prohibited without the permission of the copyright holder.
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