Integration of novel approaches demonstrates simultaneous metabolic inactivation and CAR-mediated hepatocarcinogenesis of a nitrification inhibitor

Publication date: Available online 28 October 2017 Source:Toxicology Reports Author(s): Jessica L. LaRocca, Reza J. Rasoulpour, B.Bhaskar Gollapudi, David L. Eisenbrandt, Lynea A. Murphy, Matthew J. LeBaron Nitrapyrin, a nitrification inhibitor, produces liver tumors in mice at high doses. Several experiments were performed to investigate molecular, cellular, and apical endpoints to define the key events leading to the tumor formation. These data support a mode-of-action (MoA) characterized by constitutive androstane receptor (CAR) nuclear receptor (NR) activation, increased hepatocellular proliferation leading to hepatocellular foci and tumor formation. Specifically, nitrapyrin induced a dose-related increase in the Cyp2b10/CAR-associated transcript and protein. Interestingly, the corresponding enzyme activity (7-pentoxyresorufin-O-dealkylase (PROD) was not enhanced due to nitrapyrin-mediated suicide inhibition of PROD activity. Nitrapyrin exposure elicited a clear dose-responsive increase in hepatocellular proliferation in wild-type mice, but not in CAR knock-out mice informing that CAR activation is an obligatory key event in this test material induced hepatocarcinogenesis. Furthermore, nitrapyrin exposure induced a clear, concentration-responsive increase in cell proliferation in the mouse, but not human, hepatocytes in vitro. Evaluation of the data from repeat-dose and MoA studies by the Bradford Hill criteria and a Human Relevance Framework (HRF) suggested that ...

Source: Toxicology Reports - October 28, 2017 Category: Toxicology Source Type: research