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 were dosed orally with
fenclozic acid for 7 days at 100 mg kg-1 day-1. 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-1 day-1. 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.