Regulation of the CYP3A4 and CYP3A7 Promoters by Members of the Nuclear Factor I Transcription Factor Family

Riffel, Amanda K.; Schuenemann, Eric; Vyhlidal, Carrie A.

doi:10.1124/mol.109.055699

Cited by 23 publications

(11 citation statements)

References 33 publications

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“…3C), HNF3b does not bind, whereas YY1 is capable of binding adjacent sequences of the CYP3A4 promoter. In addition, we have shown that members of the NF1 family bind to the region of the CYP3A7 proximal promoter that is differentially methylated during development as well as to the similar sequences from the CYP3A4 promoter (Riffel et al, 2009); however, members of the NF1 transcription factor family differentially affect the activity of the CYP3A4 and CYP3A7 proximal promoters in reporter assays in transiently transfected HepG2 cells whereby the transcriptional activity of the CYP3A4 promoter is increased by members of the NF1 family and the transcriptional activity of the CYP3A7 proximal promoter is decreased (Riffel et al, 2009).…”

Section: Downloaded Frommentioning

confidence: 99%

Dynamics of Cytosine Methylation in the Proximal Promoters of CYP3A4 and CYP3A7 in Pediatric and Prenatal Livers

Vyhlidal

et al. 2016

Drug Metabolism and Disposition

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Members of the human CYP3A family of metabolizing enzymes exhibit developmental changes in expression whereby CYP3A7 is expressed in fetal tissues, followed by a transition to expression of CYP3A4 in the first months of life. Despite knowledge about the general pattern of CYP3A activity in human development, the mechanisms that regulate developmental expression remain poorly understood. Epigenetic changes, including cytosine methylation, have been suggested to play a role in the regulation of CYP3A expression. The objective of this study was to investigate changes in cytosine methylation of the CYP3A4 and CYP3A7 genes in human pediatric and prenatal livers. The methylation status of cytosinephospho-guanine dinucleotides was determined in 16 pediatric liver samples using methyl-seq and confirmed by bisulfite sequencing of 48 pediatric and 34 prenatal liver samples. Samples were separated by age into five groups (prenatal, < 1 year of age, 1.8-6 years, 7-11 years, and 12-17 years). Methyl-seq anaylsis revealed that cytosines in the proximal promoter of CYP3A7 are hypomethylated in neonates compared with adolescents (P < 0.001). In contrast, a cytosine 383 base pair upstream of CYP3A4 is hypermethylated in liver samples from neonates compared with adolescents (P = 0.00001). Developmental changes in methylation of cytosines in the proximal promoters of CYP3A4 and CYP3A7 in pediatric livers were confirmed by bisulfite sequencing. In addition, the methylation status of cytosine in the CYP3A4 and CYP3A7 proximal promoters correlated with changes in developmental expression of mRNA for the two enzymes.

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Section: Downloaded Frommentioning

confidence: 99%

Dynamics of Cytosine Methylation in the Proximal Promoters of CYP3A4 and CYP3A7 in Pediatric and Prenatal Livers

Vyhlidal

et al. 2016

Drug Metabolism and Disposition

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“…Recent data demonstrate that cytochrome CYP3A4 is functionally expressed at the drug resistant, epileptic BBB [23,24]. CYP3A4 oxidizes a large group of xenobiotics, including first generation AEDs [31,34,35]. CYP3A isoforms in humans include 3A3, 3A4, 3A5 and 3A7, sharing at least 85% amino acid sequence homology [36].…”

Section: New Vistas On Drug Biotransformation: Brain P450 Enzymesmentioning

confidence: 99%

Blood-Brain Barrier P450 Enzymes and Multidrug Transporters in Drug Resistance: A Synergistic Role in Neurological Diseases

Ghosh¹

2011

CDM

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Drug penetration into the central nervous system (CNS) is controlled by the blood-brain barrier (BBB). Even though a number of strategies to circumvent the BBB and to improve drug access have been developed, drug resistance in CNS diseases remains an unmet clinical problem. We here review the mechanisms by which a healthy or pathological BBB influences drug distribution in the brain, with emphasis on the role of P450 metabolic enzymes and multi-drug transporter (MDT) proteins. In addition to the classic hepatic and gut biotransformation pathways, CNS expression of P450 enzymes may bear pharmacokinetic and pharmacodynamic significance exerting a metabolic activity and transforming parent drugs into specific products. We propose these mechanisms to play a major role in CNS drug resistant pathologies including refractory forms of epilepsy.Changes in the cerebrovascular hemodynamic conditions can affect expression of P450 enzymes and MDT proteins. This should be taken into account when developing in vitro experimental approaches to reproduce the physiological or pathological properties of the BBB. Finally, a link between P450 and MDT expression in the diseased brain and cell survival is discussed. KeywordsBlood-brain barrier; drug resistant epilepsy; multidrug transporters proteins (MDT); P450 enzymes THE BLOOD-BRAIN BARRIER: A BRIEF OVERVIEWThe brain microvascular endothelial cells that constitute the blood-brain barrier (BBB) are responsible for the passage of xenobiotics and nutrients from the blood into the brain parenchyma, and vice versa. At the cellular level, the BBB consists of endothelial cells HHS Public Access DRUG RESISTANCE IN CNS DISEASESDrug resistance in brain diseases is an unsolved clinical problem. For example, drug resistant epilepsy affects approximately 20-25% of epileptics. According to the recent consensus of the International League Against Epilepsy (ILAE), "drug resistant epilepsy is defined with the failure of adequate trials of two appropriately chosen antiepileptic drugs, whether as monotherapies or in combination, to achieve sustained seizure freedom" [7]. In the past two decades, new antiepileptic drugs (AEDs) have been developed but no major reduction in the percentage of drug-resistant patients has been achieved [8,9]. The complexity of the drug resistant epileptic phenotype reflects the nature of the pathophysiological process, its possible evolution over time and individual sensitivity to drugs. In order to explain the mechanisms underlying the drug resistant condition, a pharmacokinetic and a pharmacodynamic hypothesis were proposed more than a decade ago. AED therapeutic failure may thus be due to a modification of neuronal targets (pharmacodynamic hypothesis) [10][11][12][13] or to inadequate AED brain levels (pharmacokinetic hypothesis). Overexpression of multidrug transporter (MDTs) proteins at the BBB was considered to be a mechanism responsible for the possible AED brain misdistribution [11,[14][15][16][17][18]: overexpression of multi-drug transporters at the BBB...

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“…CYP3A7 is the dominant isoform in these cells compared with CYP3A4 in the human adult liver. Thus, HepG2 cells possess a phenotype most similar to that of the fetal liver (29,30). Although less suitable for predicting effects on metabolism in humans, HepG2 cells provide a system that is easy to handle and reproducible, and thus suitable for the investigation of gene regulation.…”

Section: Discussionmentioning

confidence: 99%

“…pregnane X receptor (PXR; -362/+53) (33), constitutive androstane receptor (CAR) (34), nuclear factor I (-243/-220) (29), differentially expressed in chondrocyte 1 (35) and hepatocyte nuclear factor 4a (HNF4a) (36) have been reported to account for a component of CYP3A4 inter-individual variability.…”

Section: A B a Bmentioning

confidence: 99%

Overexpression of CYP3A5 attenuates inducibility and activity of CYP3A4 in HepG2 cells

Kuang

Huang

Liu

et al. 2014

Molecular Medicine Reports

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There have been conflicting reports regarding the catalytic role of cytochrome P450 (CYP)3A5, which range from deeming it irrelevant to suggesting it is equally as important as CYP3A4, the most potent and abundant catalytic cytochrome enzyme in the human liver. This was partially attributed to the fact that CYP3A5 is highly polymorphic. However the importance of other underlying mechanisms remain unclear. The aim of the present study was to investigate the interaction between these enzymes. A human HepG2 hepatocellular line stably overexpressing CYP3A5 was constructed. The results suggested that CYP3A5 does not affect CYP3A4 expression directly. However, overexpression of CYP3A5 attenuated the inducibility of CYP3A4 in response to dexamethasone. A luciferase reporter assay indicated that this attenuation was due to a decrease in CYP3A4 promoter activity. Furthermore, a pharmacokinetic assay using quinidine and amlodipine showed that CYP3A4 enzyme activity per mg of microsomal protein was also decreased in the group overexpressing CYP3A5 compared with the dexamethasone‑induced control group. In conclusion, the current study demonstrated that CYP3A5 may affect CYP3A4 at the transcriptional level and may thus modify CYP3A4 expression and activity in the presence of substrates and inducers. The results indicate that CYPs may interact with each other under certain conditions and that this interaction may be a novel mechanism by which drug‑drug interactions are mediated.

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Regulation of the CYP3A4 and CYP3A7 Promoters by Members of the Nuclear Factor I Transcription Factor Family

Cited by 23 publications

References 33 publications

Dynamics of Cytosine Methylation in the Proximal Promoters of CYP3A4 and CYP3A7 in Pediatric and Prenatal Livers

Dynamics of Cytosine Methylation in the Proximal Promoters of CYP3A4 and CYP3A7 in Pediatric and Prenatal Livers

Blood-Brain Barrier P450 Enzymes and Multidrug Transporters in Drug Resistance: A Synergistic Role in Neurological Diseases

Overexpression of CYP3A5 attenuates inducibility and activity of CYP3A4 in HepG2 cells

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