It is accepted that acetominiphen (APAP) hepatocellular injury requires bioactivation by cytochromes P450 (P450s), but this remains unproven in primary mouse hepatic parenchymal cells (HPCs). The present study evaluated APAP cytotoxicity and APAP-protein adducts (a biomarker of metabolic bioactivation) using primary mouse HPCs in the presence and absence of a broad-spectrum inhibitor of P450s, 1-aminobenzotriazole (1-ABT). 1-ABT abolished formation of APAP-protein adducts at all concentrations tested, but eliminated cytotoxicity only at the low concentrations, indicating the presence of a P450-independent mechanism at larger APAP concentrations. P450-independent cell death was delayed in onset relative to toxicity observed at smaller concentrations and was related to p-aminophenol formation. In conclusion, APAP hepatocellular injury in vitro occurs by at least two mechanisms, and these findings should be considered when interpreting results from APAP cytotoxicity studies in vitro and in selecting APAP concentrations for use in such studies.
See article at J Pharmacol Exp Ther 2015, 354:230–237.
- Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics