Dexamethasone controls aryl hydrocarbon receptor (AhR)-mediated CYP1A1 and CYP1A2 expression and activity in primary cultures of human hepatocytes

Vrzal, Radim; Stejskalová, Lucie; Monostory, Katalin; Maurel, Patrick; Bachleda, Petr; Pávek, Petr; Dvořák, Zdeněk

doi:10.1016/j.cbi.2008.10.035

Cited by 71 publications

(55 citation statements)

References 32 publications

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“…These findings show that dexamethasone controls CYP1A1 expression in human hepatocytes and HepG2 cells through interactive regulatory crosstalk between GR and AHR receptors. The cross-reaction occurs only when both the AHR and GR are activated [113,114]. In extrahepatic tissues, gefitinib and erlotinib antineoplastic drugs are metabolized by CYP1A1 and CYP1A2.…”

Section: Car and Pxr (See Chapter Pxr)mentioning

confidence: 99%

Role of xenobiotic metabolism in cancer: involvement of transcriptional and miRNA regulation of P450s

Tamási

Monostory

Prough

et al. 2010

Cell. Mol. Life Sci.

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Cytochrome P450 enzymes (P450s) are important targets in cancer, due to their role in xenobiotic metabolism. Since P450s are the "bridges" between the environment and our body, their function can be linked in many ways to carcinogenesis: they activate dietary and environmental components to ultimate carcinogens (i), the cancer tissue maintains its drug resistance with altered expression of P450s (ii), P450s metabolize (sometimes activate) drugs used for cancer treatment (iii) and they are potential targets for anticancer therapy (iiii). These highly polymorphic enzymes are regulated at multiple molecular levels. Regulation is as important as genetic difference in the existing individual variability in P450 activity. In this review, examples of the transcriptional (DNA methylation, histone modification, modulation by xenosensors) and post-transcriptional (miRNA) regulation will be presented and thereby introduce potential molecular targets at which the metabolism of anticancer drugs, the elimination of cancerogenes or the progress of carcinogenesis could be affected.

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Section: Car and Pxr (See Chapter Pxr)mentioning

confidence: 99%

Role of xenobiotic metabolism in cancer: involvement of transcriptional and miRNA regulation of P450s

Tamási

Monostory

Prough

et al. 2010

Cell. Mol. Life Sci.

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“…1) with respect to newly discovered human miRNAs and advances in bioinformatic prediction algorithms. (Pascussi et al, 2003;Vrzal et al, 2009;Pavek et al, 2010). Using four different prediction programs, we found that all NRs selected for our study can be predicted to be regulated by miRNAs (Table 1 and Fig.…”

Section: Resultsmentioning

confidence: 98%

Bioinformatic analysis of miRNAs targeting the key nuclear receptors regulating CYP3A4 gene expression: The challenge of the CYP3A4 "missing heritability" enigma

2015

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Cytochrome P450Metabolism a b s t r a c tThe expression of the main cytochrome P450 enzyme CYP3A4 displays enormous interindividual variability. Studies addressing the genetic variability of either the CYP3A4 gene itself or its key transcription factors have not found any crucial polymorphism contributing to this variability in expression, a phenomenon is referred to as the ''missing heritability of CYP3A4 variability.'' Several reports have recently described microRNAs (miRNAs) targeting the CYP3A4 gene and/or its major transcription factors.A comprehensive bioinformatic analysis was performed using the miRDB, PITA, miRanda and TargetScan programs in the search for hypothetical miRNAs targeting 3 0 -untranslated regions of PXR, CAR, VDR, HNF4a, RXRa, SHP and GRa genes controlling CYP3A4 expression.We propose several novel miRNAs identified parallelly by at least three algorithms to the target analyzed genes. In particular, we found novel promising miRNAs which may be involved in the indirect PXR-mediated CYP3A4 gene expression such as miR-18a and miR18b, miR-449a, miR-449b and miR-34a. We also hypothesize that some miRNAs may play the role of a master regulator of NRs since they are predicted to target more than three genes.The identification of miRNAs determining CYP3A4 interindividual variability might be an important step toward progress in pharmacogenetics and personalized medicine.

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“…LH21 hepatocyte preparation was described in our previous paper 30 . Hepatocytes were isolated as described previously 31 .…”

Section: Primary Human Hepatocyte Culturesmentioning

confidence: 99%

Valproate activates ERK signaling pathway in primary human hepatocytes

Bitman¹,

Vrzal²,

Dvořák³

et al. 2014

Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub

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Aim. Valproic acid (VPA) is a widely-used anticonvulsant and mood-stabilizing agent. VPA is also known to inhibit histone deacetylases (HDACs) affecting the expression of numerous genes. Methods. In the present study, we examined the effect of VPA on the extracellular signal-related kinase (ERK, p42/p44) pathway (Ras-Raf-MEK-ERK) belonging to the mitogen-activated protein kinases (MAPKs) pathways in primary human hepatocytes. In the liver, the pathway is associated with progression of hepatocellular carcinoma. Results. We found that VPA in a therapeutically relevant concentration (500 μM) activates the ERK pathway, as indicated by increased ERK Thr202/Tyr204 phosphorylation. Interestingly, a prototype HDAC inhibitor, trichostatin A, also activated ERK phosphorylation in primary human hepatocytes. These data suggest that HDAC inhibition might be the primary stimulus for ERK pathway activation in primary human hepatocytes. Notably, U0126, a MEK1 inhibitor, was ineffective in inhibiting ERK pathway activation, likely due to its metabolic deactivation in metabolically competent primary human hepatocytes. Conclusion. We conclude that VPA activates the ERK pathway in primary human hepatocytes.

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Dexamethasone controls aryl hydrocarbon receptor (AhR)-mediated CYP1A1 and CYP1A2 expression and activity in primary cultures of human hepatocytes

Cited by 71 publications

References 32 publications

Role of xenobiotic metabolism in cancer: involvement of transcriptional and miRNA regulation of P450s

Role of xenobiotic metabolism in cancer: involvement of transcriptional and miRNA regulation of P450s

Bioinformatic analysis of miRNAs targeting the key nuclear receptors regulating CYP3A4 gene expression: The challenge of the CYP3A4 "missing heritability" enigma

Valproate activates ERK signaling pathway in primary human hepatocytes

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