Phenobarbital Suppresses Growth and Accelerates Restoration of Differentiation Markers of Primary Culture Rat Hepatocytes in the Chemically Defined Hepatocyte Growth Medium Containing Hepatocyte Growth Factor and Epidermal Growth Factor

Miyazaki, Masahiro; Mars, Wendy M.; Runge, Dieter; Kim, Tae‐Hyoung; Bowen, William C.; Michalopoulos, George K.

doi:10.1006/excr.1998.4085

Cited by 49 publications

(16 citation statements)

References 44 publications

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“…However, the degree of differentiation measured by absence of immature markers such as αFP and CK19 was higher when cells were also treated with HGF. This is consistent with the observation that FGF-4 is important in initial endoderm patterning and may play a role in endoderm specification (23) and that HGF induces differentiation of hepatocytes that are not actively proliferating (28)(29)(30)(31). Differentiation to cells with a hepatocyte phenotype was seen only when cells were seeded at high confluence, which may cause a postmitotic state required for differentiation in the presence of HGF.…”

Section: Discussionsupporting

confidence: 90%

Multipotent adult progenitor cells from bone marrow differentiate into functional hepatocyte-like cells

Schwartz¹,

Reyes²,

Koodie³

et al. 2002

J. Clin. Invest.

232

225

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Section: Discussionsupporting

confidence: 90%

Multipotent adult progenitor cells from bone marrow differentiate into functional hepatocyte-like cells

Schwartz¹,

Reyes²,

Koodie³

et al. 2002

J. Clin. Invest.

232

225

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“…Our laboratory has previously shown that PB induces or maintains differentiation and high levels of HNF-4␣ DNA-binding activity as well as cytochrome P450s in cultured rat hepatocytes. 12 To determine whether HNF-4␣ induction was physiologically relevant in vivo, we analyzed its expression in mouse liver following a single injection of PB (100 mg/kg, i.p.). Western blot analysis of liver nuclear protein extracts revealed a dramatic elevation in HNF-4␣ protein expression 2-4 hours post-PB in wild-type mice (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Treat-ment of the cultures with PB results in stabilization of the differentiated hepatocyte phenotype, as assessed by many differentiated functions including expression of albumin and cytochrome P450 family members and metabolic activities. 12 PB treatment in culture also is associated with decreased response to hepatocyte mitogens, including TGF␣ and HGF. 13 The mechanisms by which PB exerts all these complex effects in hepatocytes are not clear.…”

mentioning

confidence: 99%

Phenobarbital regulates nuclear expression of HNF-4α in mouse and rat hepatocytes independent of CAR and PXR

Bell

Michalopoulos

2006

Hepatology

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Phenobarbital is a lipophilic molecule used as a sedative and antiepileptic drug that elicits a multitude of effects in the liver, including gross liver enlargement, hepatocyte hypertrophy, and induced expression of drug-metabolizing enzymes and other liver-specific genes. The constitutive androstane receptor (CAR; NR1I3) and to a lesser extent the pregnane X receptor (PXR; NR1I2) are responsible for mediating induction of many phenobarbital-responsive genes. However, CAR-mediated transcriptional control of some genes is critically dependent on hepatocyte nuclear factor 4 alpha (HNF-4␣; NR2A1), which itself regulates multiple liver-specific genes involved in hepatic growth, metabolism, and differentiation. We studied the effects of phenobarbital on HNF-4␣ expression in hepatocytes and provide evidence that HNF-4␣ nuclear expression is regulated in response to phenobarbital. Realtime polymerase chain reaction analyses revealed that HNF-4␣ mRNA is modestly upregulated by phenobarbital. In addition, nuclear expression of HNF-4␣ protein is significantly elevated 3 hours after the administration of phenobarbital in wild-type, CAR ؊/؊ , and CAR ؊/؊ /PXR ؊/؊ mice. In vitro analysis revealed that phenobarbital-induced HNF-4␣ expression is both time-and dose dependent. In addition, the phosphatase inhibitor okadaic acid and the Ca 2؉ /calmodulin-dependent protein kinase II inhibitor KN62 block nuclear induction of HNF-4␣ by phenobarbital. Furthermore, HNF-4␣ nuclear expression is enhanced by inhibition of cyclic AMP-dependent protein kinase A. In conclusion, induced nuclear expression of HNF-4␣ and CAR is an integral part of the phenobarbital response, aimed at coordinated regulation of genes involved in drug metabolism and detoxification as well as maintenance of liver function. (HEPATOLOGY 2006;44: 186-194.) P henobarbital (PB) is an antiepileptic drug and is the prototype of a large family of lipophilic PB-like compounds that have profound effects in the liver. Its effects on liver physiology are typified by hepatic hypertrophy, hyperproliferation of the smooth endoplasmic reticulum, and induction or repression of numerous genes, especially the genes of cytochrome P450 enzymes. 1-3 Hepatic hypertrophy induced by PB is mediated by a moderate increase in hepatocyte DNA synthesis and dramatic enlargement of individual hepatocytes. 4,5 Hepatic enlargement subsides after PB withdrawal and this decrease in liver size is mediated by hepatocyte apoptosis. 6 Liver regeneration in response to partial hepatectomy is markedly diminished in PB-treated rat and mouse livers. 7,8 PB is also one of the most effective liver tumor promoters in both rats and mice. The mechanism of liver tumor promotion by PB is not understood; however, there is evidence that PB affects EGF signaling. 9 . Furthermore, TGF␤1 receptors I, II, and III are specifically down-regulated in early neoplastic lesions following treatment with PB. 10,11 It has been hypothesized that the inhibition of DNA synthesis in normal hepatocytes gives a proliferative advant...

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“…Mouse primary hepatocytes were isolated from 6-week-old ddY mice as previously described [11] but with minor modifications. Briefly, the liver was perfused with Hanks' balanced salt solutions (HBSS) containing 0.5 mM ethylene glycol tetra-acetic acid and 10 mM 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid at 37°C followed by perfusion with HBSS containing 5 mM CaCl 2 and 0.05% collagen I (Worthington Bio.…”

Section: Cell Culturementioning

confidence: 99%

Acetoacetyl-CoA synthetase, a ketone body-utilizing enzyme, is controlled by SREBP-2 and affects serum cholesterol levels

Hasegawa

Noda

et al. 2012

Molecular Genetics and Metabolism

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Phenobarbital Suppresses Growth and Accelerates Restoration of Differentiation Markers of Primary Culture Rat Hepatocytes in the Chemically Defined Hepatocyte Growth Medium Containing Hepatocyte Growth Factor and Epidermal Growth Factor

Cited by 49 publications

References 44 publications

Multipotent adult progenitor cells from bone marrow differentiate into functional hepatocyte-like cells

Multipotent adult progenitor cells from bone marrow differentiate into functional hepatocyte-like cells

Phenobarbital regulates nuclear expression of HNF-4α in mouse and rat hepatocytes independent of CAR and PXR

Acetoacetyl-CoA synthetase, a ketone body-utilizing enzyme, is controlled by SREBP-2 and affects serum cholesterol levels

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