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have become available, providing new opportunities for the analysis of potential species differences (scheer et al. 2008; scheer and Wolf 2013). The impact of CAr humanization on hepatic effects of PB has been addressed in different publications; after short-term PB treatment, Huang et al. (2005) show DNA synthesis in livers of humanized CAr mice (hCAr; in some of the experiments cited in the following, mice with humanized CAr and PXr were used, but are referred to as hCAr in the following for the sake of clarity) after treatment with PB. By contrast, results from another study indicate that hCAr does not support the hyperplastic response (ross et al. 2010) and a slight but significant increase in hepatocellular proliferation was observed in wild type (WT) but not hCAr mice after administration of sulfoxaflor (leBaron et al. 2013). The reason for these discrepant findings is still unclear. Thus, when considered together, these publications do not clarify the question whether hCAr has the potential to induce hepatocellular proliferation. Due to their short-term study design, the question of tumorigenesis is not addressed by these studies. Very recently, the proliferative and tumor-promoting effects of PB in hCAr mice have been addressed in two comprehensive studies; the first publication deals with the effects of PB for up to 90 days of exposure (luisier et al. 2014), while the second paper contains the results of a longterm tumor initiation/promotion carcinogenesis experiment (Braeuning et al. 2014). In the study by luisier et al. (2014), a broad-spectrum transcriptomic approach was used to detect possible differences between hCAr and WT mice in their response to PB. 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). Mechanistically, it has been proposed that species differences in the induction of hepatocellular proliferation by PB might underlie the observed discrepancy in tumor induction (elcombe et al. 2014). The proliferative response of rodent hepatocytes following PB treatment in vitro is not observed in comparable cultures of their human counterparts (Parzefall et al. 1991). An inseparable correlation of PB-induced proliferation and tumor growth, however, cannot be assumed with absolute certainty; in mice, PB exclusively promotes the outgrowth of a very distinct population of tumors, which carry activating mutations in the β-catenin gene Ctnnb1 (Aydinlik et al. 2001). Accordingly, tumor promotion by PB is absent from mice with hepatocyte-specific knockout of Ctnnb1 (rignall et al. 2011), which, however, still exhibit a proliferative response (Braeuning et al. 2011). studying tumor promotion by PB in rodents has contributed to our understanding of the mechanisms of nongenotoxic carcinogenesis, but has not been able to definitely answer the question of human relevance of these findings. recently, humanized mice, which express the human versions of certain xeno-sensing nuclear receptors,

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