The effect of phenobarbital on the transcriptional activity of liver

Hardwick, James P.; Schwalm, Fritz E.; Richardson, Arlan

doi:10.1042/bj2100599

Cited by 10 publications

(3 citation statements)

References 26 publications

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“…However, whereas transcriptional activation of the cytochrome P-450 IIB gene was detected only a few hours after a single administration of PB, induction of GST required several days of regular phenobarbital treatment. These kinetic differences could be explained as follows: in the case of cytochrome P-450 IIB, phenobarbital seems to act essentially at the transcriptional level (34)(35)(36)(37), whereas in GST induction posttranscriptional mechanisms predominate (38). With regard to AGP modulation, direct transcriptional activation by PB seems to predominate (19), and the lag time before increased gene expression could be the consequence of a more complex pathway involving several intermediate steps.…”

Section: Discussionmentioning

confidence: 99%

Phenobarbital induction of α1-acid glycoprotein in primary rat hepatocyte cultures

et al. 1994

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The serum level of rat alpha 1-acid glycoprotein is significantly increased by treatment with phenobarbital, and in vivo studies have shown that phenobarbital seems to act mainly at the transcriptional level. To show the direct mediating effect of phenobarbital on alpha 1-acid glycoprotein gene expression, we investigated the ability of primary cultured rat hepatocytes to respond to in vitro phenobarbital administration. Phenobarbital increased both alpha 1 acid glycoprotein secretion and corresponding mRNA levels in primary rat hepatocytes cultured on matrigel. Used in combination with interleukin-1, interleukin-6 and dexamethasone, phenobarbital had an additive or synergistic effect on alpha 1-acid glycoprotein synthesis. These results show that (a) phenobarbital acts directly on hepatocytes by increasing alpha 1-acid glycoprotein gene expression and (b) this effect is mediated by a specific mechanism independent of pathways involved in alpha 1-acid glycoprotein induction by interleukin-1, interleukin-6 and glucocorticoids.

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Section: Discussionmentioning

confidence: 99%

Phenobarbital induction of α1-acid glycoprotein in primary rat hepatocyte cultures

et al. 1994

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“…The subfamily of CYP2B genes is induced by barbiturates (Fujii-Kuriyama et al 1982;Mizukami et al 1983), which are central nervous system depressants, affecting the gamma-aminobutyric acid (GABA) system via modulating GABA A receptors. Hepatic transcription of CYP2B genes is highly inducible by phenobarbital (PB) and PB-like inducers (Adesnik et al 1981;Hardwick et al 1983;Gervot et al 1999) through the constitutive androstane receptor (CAR), pregnane X receptor (PXR) (Sueyoshi et al 1999;Moore et al 2000) and glucocorticoids receptor (GR) (Wang and Negishi 2003). There is growing evidence for crosstalk between CAR, PXR, and GR nuclear receptor signaling pathways that regulate cytochrome P450 genes (Kodama et al 2004;Oladimeji et al 2016).…”

Section: Regulationmentioning

confidence: 99%

Cytochrome P450 expression and regulation in the brain

Kuban

Daniel

2020

Drug Metabolism Reviews

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The regulation of brain cytochrome P450 enzymes (CYPs) is different compared with respective hepatic enzymes. This may result from anatomical bases and physiological functions of the two organs. The brain is composed of a variety of functional structures built of different interconnected cell types endowed with specific receptors that receive various neuronal signals from other brain regions. Those signals activate transcription factors or alter functioning of enzyme proteins. Moreover, the blood-brain barrier (BBB) does not allow free penetration of all substances from the periphery into the brain. Differences in neurotransmitter signaling, availability to endogenous and exogenous active substances, and levels of transcription factors between neuronal and hepatic cells lead to differentiated expression and susceptibility to the regulation of CYP genes in the brain and liver. Herein, we briefly describe the CYP enzymes of CYP1-3 families, their distribution in the brain, and discuss brain-specific regulation of CYP genes. In parallel, a comparison to liver CYP regulation is presented. CYP enzymes play an essential role in maintaining the levels of bioactive molecules within normal ranges. These enzymes modulate the metabolism of endogenous neurochemicals, such as neurosteroids, dopamine, serotonin, melatonin, anandamide, and exogenous substances, including psychotropics, drugs of abuse, neurotoxins, and carcinogens. The role of these enzymes is not restricted to xenobiotic-induced neurotoxicity, but they are also involved in brain physiology. Therefore, it is crucial to recognize the function and regulation of CYP enzymes in the brain to build a foundation for future medicine and neuroprotection and for personalized treatment of brain diseases.

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“…To date, no specific PB receptors have been identified, although cytoplasmic receptors for other enzyme-inducing drugs have been described (32). PB increases RNA transcription in rat liver (33) and this increase may account for the observed increases in hepatic microsoma1 enzyme synthesis. Differentiation of 3T3 L-1 cells is accompanied by the accumulation of several new rnRNAs and an increased rate of transcription may be responsible for this (34).…”

Section: Discussionmentioning

confidence: 90%

Modulation by phenobarbital of the differentiation of 3T3 preadipocytes

Parkes¹,

Hussain²,

Goldberg³

1986

Biochem. Cell Biol.

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The effect of phenobarbital upon the differentiation of two preadipocyte cell lines, 3T3 F442A and 3T3 L-1, was examined by measuring the synthesis and secretion of lipoprotein lipase. Extracellular enzyme was measured by treating intact cells with heparin, and the intracellular enzyme was subsequently assayed in cell homogenates. When confluent cultures of 3T3 F442A cells were treated with insulin, the cells underwent differentiation as indicated by increased activity of lipoprotein lipase within 6 days, followed in turn by increased levels of protein and triglyceride. Addition of phenobarbital with insulin enhanced total lipoprotein lipase, protein, and triglyceride content. The activity of lipoprotein lipase accumulated in the heparin-releasable fraction during differentiation was increased 2- to 3-fold and the intracellular enzyme was enhanced 15- to 20-fold by the addition of phenobarbital. The ability of phenobarbital to modulate differentiation was dependent upon the time of addition. When added early in the postconfluent period, there was a greater increase in lipoprotein lipase activity than when the drug was added at later times. Phenobarbital also stimulated lipoprotein lipase in differentiating 3T3 L-1 cells in the presence of insulin, although lipoprotein lipase activity was moderately enhanced by phenobarbital alone in these cells. These results suggest that phenobarbital may affect the conversion of adipoblasts into preadipocytes and thereby increase the proportion of cells susceptible to the differentiating stimulus.

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The effect of phenobarbital on the transcriptional activity of liver

Cited by 10 publications

References 26 publications

Phenobarbital induction of α1-acid glycoprotein in primary rat hepatocyte cultures

Phenobarbital induction of α1-acid glycoprotein in primary rat hepatocyte cultures

Cytochrome P450 expression and regulation in the brain

Modulation by phenobarbital of the differentiation of 3T3 preadipocytes

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