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

Abstract

Graphical abstract

Case examples of an evaluation of the human relevance of the pyrethroids/pyrethrins-induced liver tumours in rodents based on the mode of action

“…Regarding the human relevance of the CAR-mediated MOA in hepatocellular tumour production, numerous publications have concluded that the CAR-mediated MOA is qualitatively not relevant to humans, based on a lack of the key event of an increased cell proliferation in PB-induced hepatocellular tumorigenesis. 15,17,19,20,[29][30][31][32][33][36][37][38][39]58 Recently, an in vitro high content imaging-based assay was developed for the quantitative assessment of nascent DNA synthesis in primary hepatocyte cultures from mouse, rat, and human species. 59 Hepatocytes from all three species demonstrated CAR activation in response to the CAR agonists TCPOBOP, CITCO, and phenobarbital based on the increased gene expression of Cyp2b isoforms.…”

“…80 Therefore, these findings are consistent with the previous conclusion that the CARmediated MOA for rodent liver tumorigenesis is not relevant to humans. 15,17,19,20,[26][27][28][29][30][31][32][33][36][37][38]40,58,69,81…”

Application of humanized mice to toxicology studies: Evaluation of the human relevance of the mode of action for rodent liver tumor formation by activators of the constitutive androstane receptor (CAR)

“…While PB has been shown to stimulate RDS in cultured mouse and rat hepatocytes, many studies from different laboratories have demonstrated that PB does not increase RDS in cultured human hepatocytes 20 , 65 , 66 , 67 , 69 , 70 , 71 , 72 , 73 , 74 . In addition to studies with PB, a number of other nongenotoxic rodent CAR-activators, including benfluralin, metazachlor, metofluthrin, momfluorothrin, the natural pyrethrins, nitrapyrin, and sedaxane, and 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP), have also shown no increased RDS in cultured human hepatocytes 20 , 65 , 66 , 71 , 72 , 73 , 74 , 75 , 76 , 77 . While the above studies were performed with monolayer cultures (i.e., two-dimensional cultures), a study by Plummer et al.…”

“…1,4-bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP), have also shown no increased RDS in cultured human hepatocytes20,65,66,[71][72][73][74][75][76][77] . While the above studies were performed with monolayer cultures (i.e., two-dimensional cultures), a study by Plummer et al examined the effect of PB on RDS in a three-dimensional culture system and showed no increased RDS in cultured human hepatocytes78 .…”

Table1.DOCX

“…A single sex was used to minimize animal use while still comprehensively evaluating the MoA. Accordingly, the data generated in male mice were evaluated for MoA/Human Relevance Framework (HRF) and against Bradford Hill criteria and strongly support that nitrapyrin-induced mouse hepatocarcinogenesis is mediated via a CAR-NR activation MoA (Sonich-Mullin et al, 2001;Cohen et al, 2003;Meek et al, 2003;Boobis et al, 2006;Lake 2009;LaRocca et al, 2017). The MoA for CAR activation was represented by three key events.…”