Mode of action and human relevance analysis for nuclear receptor-mediated liver toxicity: A case study with phenobarbital as a model constitutive androstane receptor (CAR) activator

Clifford R. Elcombe, Richard C. Peffer, Douglas C. Wolf, Jason Bailey, Remi Bars, David Bell, Russell C. Cattley, Stephen S. Ferguson, David Geter, Amber Goetz, Jay I. Goodman, Susan Hester, Abigail Jacobs, Curtis J. Omiecinski, Rita Schoeny, Wen Xie, Brian G. Lake

Research output: Contribution to journalReview article

125 Citations (Scopus)

Abstract

The constitutive androstane receptor (CAR) and pregnane X receptor (PXR) are important nuclear receptors involved in the regulation of cellular responses from exposure to many xenobiotics and various physiological processes. Phenobarbital (PB) is a non-genotoxic indirect CAR activator, which induces cytochrome P450 (CYP) and other xenobiotic metabolizing enzymes and is known to produce liver foci/tumors in mice and rats. From literature data, a mode of action (MOA) for PB-induced rodent liver tumor formation was developed. A MOA for PXR activators was not established owing to a lack of suitable data. The key events in the PB-induced liver tumor MOA comprise activation of CAR followed by altered gene expression specific to CAR activation, increased cell proliferation, formation of altered hepatic foci and ultimately the development of liver tumors. Associative events in the MOA include altered epigenetic changes, induction of hepatic CYP2B enzymes, liver hypertrophy and decreased apoptosis; with inhibition of gap junctional intercellular communication being an associative event or modulating factor. The MOA was evaluated using the modified Bradford Hill criteria for causality and other possible MOAs were excluded. While PB produces liver tumors in rodents, important species differences were identified including a lack of cell proliferation in cultured human hepatocytes. The MOA for PB-induced rodent liver tumor formation was considered to be qualitatively not plausible for humans. This conclusion is supported by data from a number of epidemiological studies conducted in human populations chronically exposed to PB in which there is no clear evidence for increased liver tumor risk.

Original languageEnglish (US)
Pages (from-to)64-82
Number of pages19
JournalCritical Reviews in Toxicology
Volume44
Issue number1
DOIs
StatePublished - Jan 2014

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Phenobarbital
Cytoplasmic and Nuclear Receptors
Liver
Toxicity
Tumors
Neoplasms
Cell proliferation
Xenobiotics
Rodentia
Chemical activation
Cell Proliferation
constitutive androstane receptor
Physiological Phenomena
Enzymes
Gene expression
Cytochrome P-450 Enzyme System
Rats
Epigenomics
Causality
Hypertrophy

All Science Journal Classification (ASJC) codes

  • Toxicology

Cite this

Elcombe, Clifford R. ; Peffer, Richard C. ; Wolf, Douglas C. ; Bailey, Jason ; Bars, Remi ; Bell, David ; Cattley, Russell C. ; Ferguson, Stephen S. ; Geter, David ; Goetz, Amber ; Goodman, Jay I. ; Hester, Susan ; Jacobs, Abigail ; Omiecinski, Curtis J. ; Schoeny, Rita ; Xie, Wen ; Lake, Brian G. / Mode of action and human relevance analysis for nuclear receptor-mediated liver toxicity : A case study with phenobarbital as a model constitutive androstane receptor (CAR) activator. In: Critical Reviews in Toxicology. 2014 ; Vol. 44, No. 1. pp. 64-82.
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abstract = "The constitutive androstane receptor (CAR) and pregnane X receptor (PXR) are important nuclear receptors involved in the regulation of cellular responses from exposure to many xenobiotics and various physiological processes. Phenobarbital (PB) is a non-genotoxic indirect CAR activator, which induces cytochrome P450 (CYP) and other xenobiotic metabolizing enzymes and is known to produce liver foci/tumors in mice and rats. From literature data, a mode of action (MOA) for PB-induced rodent liver tumor formation was developed. A MOA for PXR activators was not established owing to a lack of suitable data. The key events in the PB-induced liver tumor MOA comprise activation of CAR followed by altered gene expression specific to CAR activation, increased cell proliferation, formation of altered hepatic foci and ultimately the development of liver tumors. Associative events in the MOA include altered epigenetic changes, induction of hepatic CYP2B enzymes, liver hypertrophy and decreased apoptosis; with inhibition of gap junctional intercellular communication being an associative event or modulating factor. The MOA was evaluated using the modified Bradford Hill criteria for causality and other possible MOAs were excluded. While PB produces liver tumors in rodents, important species differences were identified including a lack of cell proliferation in cultured human hepatocytes. The MOA for PB-induced rodent liver tumor formation was considered to be qualitatively not plausible for humans. This conclusion is supported by data from a number of epidemiological studies conducted in human populations chronically exposed to PB in which there is no clear evidence for increased liver tumor risk.",
author = "Elcombe, {Clifford R.} and Peffer, {Richard C.} and Wolf, {Douglas C.} and Jason Bailey and Remi Bars and David Bell and Cattley, {Russell C.} and Ferguson, {Stephen S.} and David Geter and Amber Goetz and Goodman, {Jay I.} and Susan Hester and Abigail Jacobs and Omiecinski, {Curtis J.} and Rita Schoeny and Wen Xie and Lake, {Brian G.}",
year = "2014",
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Elcombe, CR, Peffer, RC, Wolf, DC, Bailey, J, Bars, R, Bell, D, Cattley, RC, Ferguson, SS, Geter, D, Goetz, A, Goodman, JI, Hester, S, Jacobs, A, Omiecinski, CJ, Schoeny, R, Xie, W & Lake, BG 2014, 'Mode of action and human relevance analysis for nuclear receptor-mediated liver toxicity: A case study with phenobarbital as a model constitutive androstane receptor (CAR) activator', Critical Reviews in Toxicology, vol. 44, no. 1, pp. 64-82. https://doi.org/10.3109/10408444.2013.835786

Mode of action and human relevance analysis for nuclear receptor-mediated liver toxicity : A case study with phenobarbital as a model constitutive androstane receptor (CAR) activator. / Elcombe, Clifford R.; Peffer, Richard C.; Wolf, Douglas C.; Bailey, Jason; Bars, Remi; Bell, David; Cattley, Russell C.; Ferguson, Stephen S.; Geter, David; Goetz, Amber; Goodman, Jay I.; Hester, Susan; Jacobs, Abigail; Omiecinski, Curtis J.; Schoeny, Rita; Xie, Wen; Lake, Brian G.

In: Critical Reviews in Toxicology, Vol. 44, No. 1, 01.2014, p. 64-82.

Research output: Contribution to journalReview article

TY - JOUR

T1 - Mode of action and human relevance analysis for nuclear receptor-mediated liver toxicity

T2 - A case study with phenobarbital as a model constitutive androstane receptor (CAR) activator

AU - Elcombe, Clifford R.

AU - Peffer, Richard C.

AU - Wolf, Douglas C.

AU - Bailey, Jason

AU - Bars, Remi

AU - Bell, David

AU - Cattley, Russell C.

AU - Ferguson, Stephen S.

AU - Geter, David

AU - Goetz, Amber

AU - Goodman, Jay I.

AU - Hester, Susan

AU - Jacobs, Abigail

AU - Omiecinski, Curtis J.

AU - Schoeny, Rita

AU - Xie, Wen

AU - Lake, Brian G.

PY - 2014/1

Y1 - 2014/1

N2 - The constitutive androstane receptor (CAR) and pregnane X receptor (PXR) are important nuclear receptors involved in the regulation of cellular responses from exposure to many xenobiotics and various physiological processes. Phenobarbital (PB) is a non-genotoxic indirect CAR activator, which induces cytochrome P450 (CYP) and other xenobiotic metabolizing enzymes and is known to produce liver foci/tumors in mice and rats. From literature data, a mode of action (MOA) for PB-induced rodent liver tumor formation was developed. A MOA for PXR activators was not established owing to a lack of suitable data. The key events in the PB-induced liver tumor MOA comprise activation of CAR followed by altered gene expression specific to CAR activation, increased cell proliferation, formation of altered hepatic foci and ultimately the development of liver tumors. Associative events in the MOA include altered epigenetic changes, induction of hepatic CYP2B enzymes, liver hypertrophy and decreased apoptosis; with inhibition of gap junctional intercellular communication being an associative event or modulating factor. The MOA was evaluated using the modified Bradford Hill criteria for causality and other possible MOAs were excluded. While PB produces liver tumors in rodents, important species differences were identified including a lack of cell proliferation in cultured human hepatocytes. The MOA for PB-induced rodent liver tumor formation was considered to be qualitatively not plausible for humans. This conclusion is supported by data from a number of epidemiological studies conducted in human populations chronically exposed to PB in which there is no clear evidence for increased liver tumor risk.

AB - The constitutive androstane receptor (CAR) and pregnane X receptor (PXR) are important nuclear receptors involved in the regulation of cellular responses from exposure to many xenobiotics and various physiological processes. Phenobarbital (PB) is a non-genotoxic indirect CAR activator, which induces cytochrome P450 (CYP) and other xenobiotic metabolizing enzymes and is known to produce liver foci/tumors in mice and rats. From literature data, a mode of action (MOA) for PB-induced rodent liver tumor formation was developed. A MOA for PXR activators was not established owing to a lack of suitable data. The key events in the PB-induced liver tumor MOA comprise activation of CAR followed by altered gene expression specific to CAR activation, increased cell proliferation, formation of altered hepatic foci and ultimately the development of liver tumors. Associative events in the MOA include altered epigenetic changes, induction of hepatic CYP2B enzymes, liver hypertrophy and decreased apoptosis; with inhibition of gap junctional intercellular communication being an associative event or modulating factor. The MOA was evaluated using the modified Bradford Hill criteria for causality and other possible MOAs were excluded. While PB produces liver tumors in rodents, important species differences were identified including a lack of cell proliferation in cultured human hepatocytes. The MOA for PB-induced rodent liver tumor formation was considered to be qualitatively not plausible for humans. This conclusion is supported by data from a number of epidemiological studies conducted in human populations chronically exposed to PB in which there is no clear evidence for increased liver tumor risk.

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