Integration of novel approaches demonstrates simultaneous metabolic inactivation and CAR-mediated hepatocarcinogenesis of a nitrification inhibitor
| Autor: | B. Bhaskar Gollapudi, David L. Eisenbrandt, Lynea Murphy, Reza J. Rasoulpour, Matthew J. LeBaron, Jessica LaRocca |
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| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Health Toxicology and Mutagenesis Biology Toxicology 030226 pharmacology & pharmacy Article 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine lcsh:RA1190-1270 Constitutive androstane receptor Mode of action lcsh:Toxicology. Poisons ComputingMethodologies_COMPUTERGRAPHICS Nitrapyrin Human relevance framework In vitro Enzyme assay CAR Pesticide 030104 developmental biology chemistry Biochemistry Nuclear receptor Suicide inhibition Cancer research biology.protein Nitrification Metabolic inhibition/suicide inhibition |
| Zdroj: | Toxicology Reports Toxicology Reports, Vol 4, Iss, Pp 586-597 (2017) |
| ISSN: | 2214-7500 |
| Popis: | Graphical abstract Highlights • Nitrapyrin produces liver tumors in mice via a CAR mode-of-action. • Nitrapyrin does not increase hepatocellular proliferation in CAR knock-out mice. • Nitrapyrin increases cell proliferation in mouse, but not human, hepatocytes. • Nitrapyrin-induced mouse liver tumors are not relevant to human health risk assessment. 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 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 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 nitrapyrin-induced mouse liver tumors are not relevant to human health risk assessment because of qualitative differences between these two species. |
| Databáze: | OpenAIRE |
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