Nuclear Matrix Condensation and c-myc and c-fos Expression Are Specifically Altered in Cultured Rat Hepatocytes after Exposure to Cyproterone Acetate and Phenobarbital

Duivenvoorden, Wilhelmina; Schäfer, Reinhold; Pfeifer, Andréa; Piquet, D.; Maier, P.

doi:10.1006/bbrc.1995.2506

Cited by 3 publications

(2 citation statements)

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“…For instance, while CPA in combination with EGF increased c-myc mRNA in culture ( Fig. 8; Duivenvoorden et al 1995), it affected neither c-myc or c-fos expression in vivo (Coni et al 1990). Our present study also showed that agents acting through a variety of different signalling pathways can act on the myc gene in cultured hepatocytes.…”

Section: Discussionmentioning

confidence: 95%

Differential expression of c-fos and c-myc protooncogenes by estrogens, xenobiotics and other growth-stimulatory agents in primary rat hepatocytes

Lee

Edwards

2003

Arch Toxicol

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Mechanism(s) of tumour promotion in liver by estrogens and other xenobiotics such as alpha-hexachlorocyclohexane (HCH), 1,1,1-trichloro-2,2-bis(4-chlorophenyl)ethane (DDT) and phenobarbital (PB), are not well understood although it is clear that growth stimulation is one important element in their action. To help in characterizing mechanisms of growth control by these compounds, their effects on the expression of immediate-early protooncogenes c- fos and c- myc have been examined and compared with other compounds that stimulate DNA synthesis in primary cultures of normal rat hepatocytes. Expression of c- fos was undetectable in cultures not exposed to growth factors. Although neither epidermal growth factor (EGF) nor 17beta-estradiol (E(2)) alone had marked effects on c- fos mRNA, the two acted synergistically to cause clear c- fos expression, maximal 1-2 h after growth factor addition and when test agents were added on the first day in culture. Neither insulin nor dexamethasone alone induced c- fos mRNA but stimulation of c- fos expression by EGF plus estradiol occurred earlier in the presence of insulin, and was augmented by preincubation of cells with dexamethasone. EGF + E(2)-induced c- fos mRNA was completely abolished by actinomycin D, suggesting that transcription is the major mechanism for c- fos induction by E(2) + EGF. Compounds that strongly stimulate hepatocyte DNA synthesis such as norepinephrine, pyruvate, prolactin, glutethimide, monensin, ammonium chloride, and normal rat serum when in combination with EGF, all failed (when added with EGF) to affect c- fos mRNA expression. Thus, induction of c- fos expression may be a component of estradiol's growth stimulatory effect in cultured hepatocytes but this is not the case for other compounds that strongly stimulate DNA synthesis. Unlike c- fos mRNA, c- myc mRNA was detectable in hepatocyte cultures without added growth factor, was augmented within 2 h of exposure to EGF, and was further increased by adding E(2), other estrogens or a variety of other stimulators of DNA synthesis in hepatocytes. This suggests that increased c- myc expression may be a common effect of many of these agents in combination with EGF.

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Section: Discussionmentioning

confidence: 95%

Differential expression of c-fos and c-myc protooncogenes by estrogens, xenobiotics and other growth-stimulatory agents in primary rat hepatocytes

Lee

Edwards

2003

Arch Toxicol

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“…Interestingly, the antiandrogen cyproterone acetate, identified herein as a PXR activator, also includes liver cell proliferation, and previous attempts to determine the signaling pathway for proliferation have been futile (Menegazzi et al, 1997). Cyproterone acetate also causes DNA damage in liver (Werner et al, 1997), is a rodent liver tumor promoter (Duivenvoorden et al, 1995), and increases sensitivity of hepatocytes to undergo apoptosis (Oberhammer et al, 1996). It remains to be determined whether ligand activated PXR is involved in mediating any of these other biological activities associated with nonplanar PCBs or cyproterone acetate.…”

Section: Discussionmentioning

confidence: 95%

Environmental Xenobiotics and the Antihormones Cyproterone Acetate and Spironolactone Use the Nuclear Hormone Pregnenolone X Receptor to Activate theCYP3A23Hormone Response Element

1998

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The pregnenolone X receptor (PXR), a new member of the nuclear hormone receptor superfamily, was recently demonstrated to mediate glucocorticoid agonist and antagonist activation of a hormone response element spaced by three nucleotides (DR-3) within the rat CYP3A23 promoter. Because many other steroids and xenobiotics can up-regulate CYP3A23 expression, we determined whether some of these other regulators used PXR to activate the CYP3A23 DR-3. Transient co-transfection of LLC-PK1 cells with (CYP3A23)2-tk-CAT and mouse PXR demonstrated that the organochlorine pesticides transnonachlor and chlordane and the nonplanar polychlorinated biphenyls (PCBs) each induced the CYP3A23 DR-3 element, and this activation required PXR. Additionally, this study found that PXR is activated to induce (CYP3A23)2-tk-CAT by antihormones of several steroid classes including the antimineralocorticoid spironolactone and the antiandrogen cyproterone acetate. These studies reveal that PXR is involved in the induction of CYP3A23 by pharmacologically and structurally distinct steroids and xenobiotics. Moreover, PXR-mediated PCB activation of the (CYP3A23)2-tk-CAT may serve as a rapid assay for effects of nonplanar PCBs.

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Changes in expression of CCAAT/enhancer binding protein α (C/EBPα) and C/EBPβ in rat liver after partial hepatectomy but not after treatment with cyproterone acetate

Skrtic¹,

Ekberg²,

Wallenius³

et al. 1997

Journal of Hepatology

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Nuclear Matrix Condensation and c-myc and c-fos Expression Are Specifically Altered in Cultured Rat Hepatocytes after Exposure to Cyproterone Acetate and Phenobarbital

Cited by 3 publications

References 0 publications

Differential expression of c-fos and c-myc protooncogenes by estrogens, xenobiotics and other growth-stimulatory agents in primary rat hepatocytes

Differential expression of c-fos and c-myc protooncogenes by estrogens, xenobiotics and other growth-stimulatory agents in primary rat hepatocytes

Environmental Xenobiotics and the Antihormones Cyproterone Acetate and Spironolactone Use the Nuclear Hormone Pregnenolone X Receptor to Activate theCYP3A23Hormone Response Element

Changes in expression of CCAAT/enhancer binding protein α (C/EBPα) and C/EBPβ in rat liver after partial hepatectomy but not after treatment with cyproterone acetate

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