Using Nuclear Receptor Activity to Stratify Hepatocarcinogens

Abstract

BackgroundNuclear receptors (NR) are a superfamily of ligand-activated transcription factors that control a range of cellular processes. Persistent stimulation of some NR is a non-genotoxic mechanism of rodent liver cancer with unclear relevance to humans. Here we report on a systematic analysis of new in vitro human NR activity data on 309 environmental chemicals in relationship to their liver cancer-related chronic outcomes in rodents.ResultsThe effects of 309 environmental chemicals on human constitutive androstane receptors (CAR/NR1I3), pregnane X receptor (PXR/NR1I2), aryl hydrocarbon receptor (AhR), peroxisome proliferator-activated receptors (PPAR/NR1C), liver X receptors (LXR/NR1H), retinoic X receptors (RXR/NR2B) and steroid receptors (SR/NR3) were determined using in vitro data. Hepatic histopathology, observed in rodents after two years of chronic treatment for 171 of the 309 chemicals, was summarized by a cancer lesion progression grade. Chemicals that caused proliferative liver lesions in both rat and mouse were generally more active for the human receptors, relative to the compounds that only affected one rodent species, and these changes were significant for PPAR (p0.001), PXR (p0.01) and CAR (p0.05). Though most chemicals exhibited receptor promiscuity, multivariate analysis clustered them into relatively few NR activity combinations. The human NR activity pattern of chemicals weakly associated with the severity of rodent liver cancer lesion progression (p0.05).ConclusionsThe rodent carcinogens had higher in vitro potency for human NR relative to non-carcinogens. Structurally diverse chemicals with similar NR promiscuity patterns weakly associated with the severity of rodent liver cancer progression. While these results do not prove the role of NR activation in human liver cancer, they do have implications for nuclear receptor chemical biology and provide insights into putative toxicity pathways. More importantly, these findings suggest the utility of in vitro assays for stratifying environmental contaminants based on a combination of human bioactivity and rodent toxicity.

Recent advances in 2D and 3D in vitro systems using primary hepatocytes, alternative hepatocyte sources and non-parenchymal liver cells and their use in investigating mechanisms of hepatotoxicity, cell signaling and ADME

“…Future uses for primary liver cell models might also include high-throughput screening assays in programs such as the USEPA ToxCast program (Judson et al 2011; Shah et al 2011). There is an ongoing effort in toxicology to find cheaper and faster ways to identify potentially toxic chemicals without using large numbers of animals.…”

Nuclear receptors and nonalcoholic fatty liver disease

“…Relatively less is known about LXR and hepatocarcinogenesis. While some carcinogenic environmental chemicals activate LXR, they may simultaneously activate other class II nuclear receptors as well, making it difficult to determine the exact role of LXR in tumor development [183]. …”

In Vitro and Modelling Approaches to Risk Assessment from the U.S. Environmental Protection Agency ToxCast Programme

“…In total, there are up to 700 assays or assay end-points being used as part of the ToxCast programme. These cover a large range of technologies, including cell-free biochemical assays, assays targeting nuclear and other receptors and other molecular targets, assays measuring downstream integrated cell processes and model organisms (especially zebrafish) [5,6,[13][14][15][16][17][18][19][20][21][22][23][24]. The complete set of assay descriptions can be found at the ToxCast website.…”