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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, C., R. Peffer, D. Wolf, J. Bailey, R. Bars, D. Bell, R. Cattley, S. Ferguson, D. Geter, A. Goetz, J. Goodman, S. Hester, A. Jacobs, C. Omiecinski, R. Schoeny, W. Xie, AND B. Lake. 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. CRC Press LLC, Boca Raton, FL, 44(1):64-82, (2014).
Many non-genotoxic chemicals, such as phenobarbital (phenobarbitone, PB) produce liver tumors in rats and mice (Gold et al., 2001; Grasso and Hinton, 1991; Huff et al., 1991) In recent years, frameworks for analysing the modes of action (MOA) by which such chemicals produce liver tumors have been developed.
The constitutive androstane receptor (CAR) and pregnane X receptor (PXR) are key nuclear receptors involved in the regulation of cellular responses. to 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 metabolising enzymes and is known to produce liver 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, altered gene expression specific to CAR activation, increased cell proliferation, decreased apoptosis, formation of altered hepatic foci and ultimately the development of liver tumors. Associative events in the MOA included altered epigenetic changes, induction of hepatic CYP2B enzymes and liver hypertrophy; with inhibition of gap junctional intercellular communication being an associative event or modulating factor. The MOA was evaluated based on 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 effect on replicative DNA synthesis in cultured human hepatocytes. The MOA for PB-induced liver tumor formation was considered to be likely not qualitatively plausible for humans. This conclusion is supported by data from a number of epidemiological studies conducted in human populations chronically exposed to PB where there is no clear evidence for increased liver tumor risk.