Improved hepatic physiology in hepatic cytochrome P450 reductase null (HRN™) mice dosed orally with fenclozic acid

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Title: Improved hepatic physiology in hepatic cytochrome P450 reductase null (HRN™) mice dosed orally with fenclozic acid
Author(s): Akingbasote, JA
Foster, AJ
Jones, HB
David, R
Gooderham, NJ
Wilson, ID
Gerry Kenna, J
Item Type: Journal Article
Abstract: Hepatic NADPH-cytochrome P450 oxidoreductase null (HRN™) mice exhibit no functional expression of hepatic cytochrome P450 (P450) when compared to wild type (WT) mice, but have normal hepatic and extrahepatic expression of other biotransformation enzymes. We have assessed the utility of HRN™ mice for investigation of the role of metabolic bioactivation in liver toxicity caused by the nonsteroidal anti-inflammatory drug (NSAID) fenclozic acid. In vitro studies revealed significant NADPH-dependent (i.e. P450-mediated) covalent binding of [14C]-fenclozic acid to liver microsomes from WT mice and HRN™ mice, whereas no in vitro covalent binding was observed in the presence of the UDP-glucuronyltransferase cofactor UDPGA. Oral fenclozic acid administration did not alter the liver histopathology or elevate the plasma liver enzyme activities of WT mice, or affect their hepatic miRNA contents. Livers from HRN™ mice exhibited abnormal liver histopathology (enhanced lipid accumulation, bile duct proliferation, hepatocellular degeneration, necrosis, inflammatory cell infiltration) and plasma clinical chemistry (elevated alanine aminotransferase, glutamate dehydrogenase and alkaline phosphatase activities). Modest apparent improvements in these abnormalities were observed when HRN™ mice dosed orally with fenclozic acid for 7 days at 100 mg/kg/day. Previously we observed more marked effects on liver histopathology and integrity in HRN™ mice dosed orally with the NSAID diclofenac for 7 days at 30 mg/kg/day. We conclude that HRN™ mice are valuable for assessing P450-related hepatic drug biotransformation, but not for drug toxicity studies due to underlying liver dysfunction. Nonetheless, HRN™ mice may provide novel insights into the role of inflammation in liver injury, thereby aiding its treatment.
Publication Date: 9-Nov-2016
Date of Acceptance: 7-Nov-2016
URI: http://hdl.handle.net/10044/1/42488
DOI: https://dx.doi.org/10.1039/c6tx00376a
ISSN: 2045-4538
Publisher: Royal Society of Chemistry
Start Page: 81
End Page: 88
Journal / Book Title: Toxicology Research
Volume: 6
Copyright Statement: © 2016 The Royal Society of Chemistry
Publication Status: Published
Embargo Date: 2017-11-09
Appears in Collections:Division of Surgery
Faculty of Medicine



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