Mode of action analysis for pesticide‐induced rodent liver tumours involving activation of the constitutive androstane receptor: relevance to human cancer risk

Abstract

A number of non-genotoxic chemicals, including some pesticides, have been shown to increase the incidence of liver tumours in rats and/or mice. Frameworks for analysing the modes of action (MOAs) by which chemicals produce liver tumours in rodents and the relevance of such tumour data for human risk assessment have now been established. One common MOA for rodent liver tumour formation by non-genotoxic chemicals involves activation of the constitutive androstane receptor (CAR). Key and associative events for a CAR-activation MOA include receptor activation, liver hypertrophy, induction of cytochrome P450 enzyme activities, increased replicative DNA synthesis, altered hepatic foci and liver tumours. While some effects of rodent CAR activators can be observed in human liver, a major species difference is that, unlike rodents, CAR activators do not increase replicative DNA synthesis in human hepatocytes. The CAR-activation MOA for rodent liver tumour formation is thus not plausible for humans, and hence such compounds do not pose a hepatocarcinogenic hazard for humans.

Evaluation of the human relevance of the constitutive androstane receptor-mediated mode of action for rat hepatocellular tumor formation by the synthetic pyrethroid momfluorothrin

“…The data obtained in these studies with the CAR activator momfluorothrin is in agreement with literature data on other CAR activators that have shown increased replicative DNA synthesis in cultured rodent hepatocytes but not in cultured human hepatocytes (Hirose et al, 2009;Lake et al, 2015;Elcombe et al, 2014;Parzefall et al, 1991;Yamada et al, 2015). Table 3 summarizes the available rat and human data for the key and associative events in the proposed MOA for momfluorothrin-induced rat liver tumour formation.…”

“…In evaluating the relevance of rodent liver tumours induced by a CAR activation MOA for humans, the key species difference is that such compounds increase replicative DNA synthesis in rodent hepatocytes but not in human hepatocytes (Cohen, 2010;Elcombe et al, 2014;Lake et al, 2015;Wood et al, 2015;Kushida et al, 2016). For human hepatocytes, in contrast to hHGF, replicative DNA synthesis was not increased by treatment with 500 and 1,000 μM NaPB, 1-1,000 μM momfluorothrin or 5-1,000 μM Z-CMCA in the present study.…”

Biphasic hCAR Inhibition-Activation by Two Aminoazo Liver Carcinogens

“…Normally phosphorylated and complexed with heat shock protein 90 (HSP90) and cytosolic CAR retention protein (CCRP) in cytosol, CAR can become activated, e.g., in mice by binding to a ligand, such as 1,4-bis [2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP), or in mice or humans by being dephosphorylated via phenobarbital-mediated recruitment of protein phosphatase 2 (PP2A), after which CAR translocates to the nucleus where it heterodimerizes with nuclear receptor RXR and then interacts with promoter complexes of target genes that regulate many physiological processes including lipid metabolism, glucose metabolism, hormonal regulation, cell growth, wound healing, and apoptosis [1][2][3][4][5][6][7]. CAR is thought to promote liver tumors in some rodents by stimulating downstream (e.g., CYP2b, Wisp, FoxM1, cMyc) receptors, multidrug transporters and resistance genes, and related epigenetic modifications (e.g., regions of altered DNA methylation) and microRNA dysregulation (e.g., miR-182 and miR-802 upregulation and miR-122 downregulation) that facilitate hepatocellular proliferation and associated shifts in energy and growth-directed metabolism [2,5,[8][9][10][11][12][13][14][15][16][17][18][19][20][21][22], particularly when coupled with -catenin activation [23].…”

Special Issue to mark the career and retirement of Professor Gerry Brooks as the Editor‐in‐Chief of Pest Management Science

“…Most of the collection of articles in this special issue have been written by former or current colleagues of Gerry, from throughout his long and illustrious career. Gerry was born in 1930 and attended school in Nottingham, England, before studying chemistry at London University.…”