Phenobarbital mechanistic data and risk assessment: Enzyme induction, enhanced cell proliferation, and tumor promotion

Liver cell proliferation and tumor promotion by phenobarbital: relevance for humans?

“…In essence, no fundamental genotype differences regarding the transcriptomic fingerprint of CAr activation is reported and the similar regulation of characteristic gene expression fingerprints related to cell division and proliferation indicates an induction of hepatocellular The anticolvulsant phenobarbital (PB) and other activators of the constitutive androstane receptor (CAr) act as transient inducers of hepatocyte proliferation and as potent nongenotoxic carcinogens in rodent liver. epidemiological studies, however, did not provide sufficient evidence for liver tumor induction by PB in humans whilst also not entirely ruling out this possibility (Whysner et al 1996;Holsapple et al 2006). The IArC has classified PB as a class 2B carcinogen (IArC 2001).…”

Human relevance framework for rodent liver tumors induced by the insecticide sulfoxaflor

“…There is uncertainty as to whether the Cyp induction is a critical step (necessary) or an indicator of chemical activity that is secondary to activation of CAR (associative). Activation of rodent CAR produces a cascade of alterations in the liver including gene transcription and increased hepatocellular proliferation in rodents, a critical event in the development of liver tumors (Whysner et al 1996, Cohen 2010, Elcombe et al 2014. In humans, PB results in activation of CAR and PXR leading to the induction of Cyp enzymes as in rodents; however, a diff erent response is induced in humans compared to that of rodents (Lambert et al 2009) and, importantly, there is no evidence of increased hepatocellular proliferation.…”

“…In humans, PB results in activation of CAR and PXR leading to the induction of Cyp enzymes as in rodents; however, a diff erent response is induced in humans compared to that of rodents (Lambert et al 2009) and, importantly, there is no evidence of increased hepatocellular proliferation. Extensive human epidemiologic studies at PB exposure levels similar to those used in rodent bioassays did not reveal increased cancer risks (Whysner et al 1996, Lamminpaa et al 2002. Based on this assessment, PB is not considered to be a hepatocarcinogen in humans.…”

“…Activation of nuclear receptors in the rodent liver, which has been traditionally associated with induction of cytochrome p450 (i.e., Cyp) enzymes, is a well-known MoA for rodent hepatocarcinogenesis with the non-genotoxic tumor promoter phenobarbital (PB) as a standard example (Whysner et al 1996, Holsapple et al 2006). More specifi cally, the MoA for CARmediated eff ects includes the following key events: (1) activation of CAR leading to Cyp isozyme induction, (2) increased hepatocellular proliferation, and (3) subsequent induction of proliferative lesions in the liver including hepatocellular foci, adenomas, and carcinomas (Cohen 2010, Elcombe et al 2014).…”

Genomic Profiling in Nuclear Receptor-Mediated Toxicity

“…Subacute administration of these compounds results in liver enlargement, hepatic hyperplasia, and induction of metabolizing enzymes, with prolonged treatment ultimately leading to liver tumor formation (Diwan et al, 1992;Whysner et al, 1996). In an effort to identify early markers of chemicalinduced carcinogenicity, CAR-activator, PB along with other nongenotoxic carcinogens (clofibrate, bemitradine, doxylamine, or methapyrilene), genotoxic carcinogens (tamoxifen or 1-acetylaminofluorene) and noncarcinogenic compounds (4-acetylaminofluoorene or isoniazid) were administered to rats for 5 days (Kramer et al, 2004) and gene expression was correlated with hepatic carcinogenicity.…”