API

Stressor: 133

Title

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Phenobarbital

Stressor Overview

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AOPs Including This Stressor

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Events Including This Stressor

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Chemical Table

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User term DTXID Preferred name Casrn jchem_inchi_key indigo_inchi_key
Phenobarbital DTXSID5021122 Phenobarbital 50-06-6 DDBREPKUVSBGFI-UHFFFAOYSA-N DDBREPKUVSBGFI-UHFFFAOYSA-N

AOP Evidence

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Enhanced hepatic clearance of thyroid hormones leading to thyroid follicular cell adenomas and carcinomas in the rat and mouse

There is no evidence text for this AOP



Constitutive androstane receptor activation leading to hepatocellular adenomas and carcinomas in the mouse and the rat

There is no evidence text for this AOP




Event Evidence

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Activation, Constitutive androstane receptor

There is no evidence text for this event.



Altered gene expression specific to CAR activation, Hepatocytes

Phenobarbital (PB)

1.         The ability of PB to induce members of the CYP2B and CYP3A subfamilies of cytochrome enzymes in the livers of rats and mice as well as a number of other genes involved in xenobiotic metabolism, cell proliferation, energy metabolism and lipid metabolism is well-established and has been demonstrated in multiple studies (Elcombe et al., 2014;  Peffer et al., 2018b;  Whysner et al., 1996;  Yamada et al., 2014). Examination of gene expression profiles of in CAR null mice revealed that not all PB-induced genes are CAR-dependent (Ueda et al., 2002).

2.         PB, TCPOBOP, CITCO were used to develop a CAR-dependent gene expression signature (83 genes) in the mouse liver that can be used to predict CAR activation. TCPOBOP (3 mg/kg body weight) was administered (i.p.) to wild-type and CAR-null mice once, followed by injection with vehicle for 2 consecutive days; CITCO (30 mg/kg body weight) and PB (100 mg/kg body weight) were administered once daily for three consecutive days; livers were isolated from mice 6 h after the last injection (Chua and Moore, 2012;  Oshida et al., 2015a). Genes that are upregulated in the CAR signature include Gadd45b and many associated with xenobiotic metabolism, including Cyp2b10 (Oshida et al., 2015a).



Increase, Mitogenic cell proliferation (hepatocytes)

Phenobarbital

1.         NaPB treatment has been shown to increase replicative DNA synthesis in cultured mouse (Haines et al., 2018c) and rat hepatocytes (Haines et al., 2018c;  Hirose et al., 2009).

2.         NaPB treatment (1 week 500-2500 ppm in the diet) was shown to significantly increase the BrdU labeling index in the livers of male CD-1 mice and male Wistar rats compared to their respective vehicle-treated controls (Yamada et al., 2014).

3.         An increase in replicative DNA synthesis was observed in male and female mice administered 1000 ppm NaPB in the diet for 1 month (Jones et al., 2009).

4.         PB at 0, 10, 50, 100 and 500 mg/kg (ppm) in the diet was administered to 8 week old male rats and male mice for 90 days. A significant induction of hepatic replicative DNA synthesis (as determined by [3H]-thymidine incorporation) was observed in the rat liver at 7 days, but had returned to control levels by 14 days. In mice, there was a significant increase in hepatic replicative DNA synthesis throughout treatment (Kolaja et al., 1996a). In both species, the most pronounced effect was observed in the centrilobular region.




Stressor Info

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Chemical/Category Description

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Characterization of Exposure

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References

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