Using nuclear receptor activity to stratify hepatocarcinogens.

<h4>Background</h4>Nuclear 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 sy...

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Autores principales:	Imran Shah, Keith Houck, Richard S Judson, Robert J Kavlock, Matthew T Martin, David M Reif, John Wambaugh, David J Dix
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2011
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/ed5c65908d7240b6ab1410db368238d9
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spelling	oai:doaj.org-article:ed5c65908d7240b6ab1410db368238d92021-11-18T06:58:51ZUsing nuclear receptor activity to stratify hepatocarcinogens.1932-620310.1371/journal.pone.0014584https://doaj.org/article/ed5c65908d7240b6ab1410db368238d92011-02-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/21339822/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203<h4>Background</h4>Nuclear 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.<h4>Results</h4>The 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).<h4>Conclusions</h4>The 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.Imran ShahKeith HouckRichard S JudsonRobert J KavlockMatthew T MartinDavid M ReifJohn WambaughDavid J DixPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 6, Iss 2, p e14584 (2011)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Imran Shah Keith Houck Richard S Judson Robert J Kavlock Matthew T Martin David M Reif John Wambaugh David J Dix Using nuclear receptor activity to stratify hepatocarcinogens.
description	<h4>Background</h4>Nuclear 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.<h4>Results</h4>The 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).<h4>Conclusions</h4>The 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.
format	article
author	Imran Shah Keith Houck Richard S Judson Robert J Kavlock Matthew T Martin David M Reif John Wambaugh David J Dix
author_facet	Imran Shah Keith Houck Richard S Judson Robert J Kavlock Matthew T Martin David M Reif John Wambaugh David J Dix
author_sort	Imran Shah
title	Using nuclear receptor activity to stratify hepatocarcinogens.
title_short	Using nuclear receptor activity to stratify hepatocarcinogens.
title_full	Using nuclear receptor activity to stratify hepatocarcinogens.
title_fullStr	Using nuclear receptor activity to stratify hepatocarcinogens.
title_full_unstemmed	Using nuclear receptor activity to stratify hepatocarcinogens.
title_sort	using nuclear receptor activity to stratify hepatocarcinogens.
publisher	Public Library of Science (PLoS)
publishDate	2011
url	https://doaj.org/article/ed5c65908d7240b6ab1410db368238d9
work_keys_str_mv	AT imranshah usingnuclearreceptoractivitytostratifyhepatocarcinogens AT keithhouck usingnuclearreceptoractivitytostratifyhepatocarcinogens AT richardsjudson usingnuclearreceptoractivitytostratifyhepatocarcinogens AT robertjkavlock usingnuclearreceptoractivitytostratifyhepatocarcinogens AT matthewtmartin usingnuclearreceptoractivitytostratifyhepatocarcinogens AT davidmreif usingnuclearreceptoractivitytostratifyhepatocarcinogens AT johnwambaugh usingnuclearreceptoractivitytostratifyhepatocarcinogens AT davidjdix usingnuclearreceptoractivitytostratifyhepatocarcinogens
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Using nuclear receptor activity to stratify hepatocarcinogens.

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