Expression and transcriptional regulation of ABC transporters and cytochromes P450 in hCMEC/D3 human cerebral microvascular endothelial cells

Dauchy, Sandrine; Miller, Florence; Couraud, Pierre‐Olivier; Weaver, Richard J.; Weksler, Babette B.; Romero, Ignacio A.; Scherrmann, Jean‐Michel; Waziers, Isabelle de; Declèves, Xavier

doi:10.1016/j.bcp.2008.11.001

Cited by 168 publications

(170 citation statements)

References 58 publications

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“…This protein is encoded by the multidrug resistance gene 1 (MDR1) and its functional complex is not only modified by internal factors but also environmental clues such as the presence of toxins. 30 Receptor mediated transport processes additionally occur at the BBB as mechanism regulating the crossing of endogenous substances. These peptide receptors may mediate processes such as transcytosis of ligands from blood to brain or from brain to blood, or only uptake into the brain capillary endothelium without further export into the brain parenchyma.…”

Section: Mechanism Of Bbb Crossing By Endogenous Substancesmentioning

confidence: 99%

Nanoparticle transport across the blood brain barrier

et al. 2016

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While the role of the blood-brain barrier (BBB) is increasingly recognized in the (development of treatments targeting neurodegenerative disorders, to date, few strategies exist that enable drug delivery of non-BBB crossing molecules directly to their site of action, the brain. However, the recent advent of Nanomedicines may provide a potent tool to implement CNS targeted delivery of active compounds. Approaches for BBB crossing are deeply investigated in relation to the pathology: among the main important diseases of the CNS, this review focuses on the application of nanomedicines to neurodegenerative disorders (Alzheimer, Parkinson and Huntington's Disease) and to other brain pathologies as epilepsy, infectious diseases, multiple sclerosis, lysosomal storage disorders, strokes.

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Section: Mechanism Of Bbb Crossing By Endogenous Substancesmentioning

confidence: 99%

Nanoparticle transport across the blood brain barrier

et al. 2016

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“…The cell line is used as an in vitro model to investigate the function and their modulation in human BBB by many laboratories (68)(69)(70)(71). A series of investigations demonstrated that the expression pattern of ATP-binding cassette transporter messenger RNAs in hCMEC/D3 cells is, at least qualitatively, similar to that of human brain microvessels (72,73). To understand the suitability and limitations of the hCMEC/D3 cell line being a BBB functional model, Ohtsuki et al (74) applied quantitative targeted proteomics to determine the protein expression levels of multiple transporters, receptors, and junction proteins in hCMEC/D3 cells and compared the results with isolated human brain microvessels.…”

Section: Examples Of Quantitative Targeted Proteomics For Membrane Trmentioning

confidence: 99%

Quantitative Targeted Proteomics for Membrane Transporter Proteins: Method and Application

Qiu

Zhang

Lai

2014

AAPS J

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Abstract. Although global proteomics has shown promise for discovery of many new proteins, biomarkers, protein modifications, and polymorphisms, targeted proteomics is emerging in the proteomics research field as a complement to untargeted shotgun proteomics, particularly when a determined set of low-abundance functional proteins need to be measured. The function and expression of proteins related to drug absorption, distribution, metabolism, and excretion (ADME) such as cytochrome P450 enzymes and membrane transporters are of great interest in biopharmaceutical research. Since the variation in ADME-related protein expression is known to be a major complicating factor encountered during in vitro-in vivo and in vivo-in vivo extrapolations (IVIVE), the accurate quantification of the ADME proteins in complex biological systems becomes a fundamental element in establishing IVIVE for pharmacokinetic predictions. In this review, we provide an overview of relevant methodologies followed by a summary of recent applications encompassing mass spectrometry-based targeted quantifications of membrane transporters.KEY WORDS: drug absorption, distribution, metabolism, and excretion (ADME); drug transporters; in vitro-in vivo and in vivo-in vivo extrapolations (IVIVE); LC-MS/MS; quantitative targeted proteomics.

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“…Evidences support the presence of CYPs in the human and rodent brain [29][30][31]: brain expression of CYP1A1, 1B1, Phase II epoxide hydrolase and UDPglucoronosyltransferase was confirmed using rodent models and human brain tissue. Finally, the expression of CYPs enzymes was demonstrated in an immortalized brain endothelial cell line [32,33]. Table 1 summarizes the patterns of expression of Phase I and II metabolic enzymes in the brain.…”

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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Expression and transcriptional regulation of ABC transporters and cytochromes P450 in hCMEC/D3 human cerebral microvascular endothelial cells

Cited by 168 publications

References 58 publications

Nanoparticle transport across the blood brain barrier

Nanoparticle transport across the blood brain barrier

Quantitative Targeted Proteomics for Membrane Transporter Proteins: Method and Application

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

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