Up‐regulation of P‐glycoprotein by HIV protease inhibitors in a human brain microvessel endothelial cell line
Identifieur interne : 000202 ( France/Analysis ); précédent : 000201; suivant : 000203Up‐regulation of P‐glycoprotein by HIV protease inhibitors in a human brain microvessel endothelial cell line
Auteurs : Jason A. Zastre [Canada] ; Gary N. Y. Chan [Canada] ; Patrick T. Ronaldson [Canada] ; Manisha Ramaswamy [Canada] ; Pierre O. Couraud [Canada, France] ; Ignacio A. Romero [Royaume-Uni] ; Babette Weksler [États-Unis] ; Moise Bendayan [Canada] ; Reina Bendayan [Canada]Source :
- Journal of Neuroscience Research [ 0360-4012 ] ; 2009-03.
English descriptors
- KwdEn :
Abstract
A major concern regarding the chronic administration of antiretroviral drugs is the potential for induction of drug efflux transporter expression (i.e., P‐glycoprotein, P‐gp) at tissue sites that can significantly affect drug distribution and treatment efficacy. Previous data have shown that the inductive effect of human immunodeficiency virus protease inhibitors (PIs) is mediated through the human orphan nuclear receptor, steroid xenobiotic receptor (SXR or hPXR). The objectives of this study were to investigate transport and inductive properties on efflux drug transporters of two PIs, atazanavir and ritonavir, at the blood–brain barrier by using a human brain microvessel endothelial cell line, hCMEC/D3. Transport properties of PIs by the drug efflux transporters P‐gp and multidrug resistance protein 1 (MRP1) were assessed by measuring the cellular uptake of 3H‐atazanavir or 3H‐ritonavir in P‐gp and MRP1 overexpressing cells as well as hCMEC/D3. Whereas the P‐gp inhibitor, PSC833, increased atazanavir and ritonavir accumulation in hCMEC/D3 cells by 2‐fold, the MRP inhibitor MK571 had no effect. P‐gp, MRP1, and hPXR expression and localization were examined by Western blot analysis and immunogold cytochemistry at the electron microscope level. Treatment of hCMEC/D3 cells for 72 hr with rifampin or SR12813 (two well‐established hPXR ligands) or PIs (atazanavir or ritonavir) resulted in an increase in P‐gp expression by 1.8‐, 6‐, and 2‐fold, respectively, with no effect observed for MRP1 expression. In hCMEC/D3 cells, cellular accumulation of these PIs appears to be primarily limited by P‐gp efflux activity. Long‐term exposure of atazanavir or ritonavir to brain microvessel endothelium may result in further limitations in brain drug permeability as a result of the up‐regulation of P‐gp expression and function. © 2008 Wiley‐Liss, Inc.
Url:
DOI: 10.1002/jnr.21898
Affiliations:
- Canada, France, Royaume-Uni, États-Unis
- Ontario, Québec, État de New York, Île-de-France
- Montréal, Paris, Toronto
- Université de Toronto
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Neurosci. Res.</title><idno type="ISSN">0360-4012</idno><idno type="eISSN">1097-4547</idno><imprint><publisher>Wiley Subscription Services, Inc., A Wiley Company</publisher><pubPlace>Hoboken</pubPlace><date type="published" when="2009-03">2009-03</date><biblScope unit="volume">87</biblScope><biblScope unit="issue">4</biblScope><biblScope unit="page" from="1023">1023</biblScope><biblScope unit="page" to="1036">1036</biblScope></imprint><idno type="ISSN">0360-4012</idno></series><idno type="istex">8FFC69AD5E42BA16B8D6B788BAFC8D7F2739E77C</idno><idno type="DOI">10.1002/jnr.21898</idno><idno type="ArticleID">JNR21898</idno></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0360-4012</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>HIV/AIDS</term><term>blood–brain barrier</term><term>drug efflux transporters</term><term>nuclear receptors</term><term>protease inhibitors</term></keywords></textClass><langUsage><language ident="en">en</language></langUsage></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">A major concern regarding the chronic administration of antiretroviral drugs is the potential for induction of drug efflux transporter expression (i.e., P‐glycoprotein, P‐gp) at tissue sites that can significantly affect drug distribution and treatment efficacy. Previous data have shown that the inductive effect of human immunodeficiency virus protease inhibitors (PIs) is mediated through the human orphan nuclear receptor, steroid xenobiotic receptor (SXR or hPXR). The objectives of this study were to investigate transport and inductive properties on efflux drug transporters of two PIs, atazanavir and ritonavir, at the blood–brain barrier by using a human brain microvessel endothelial cell line, hCMEC/D3. Transport properties of PIs by the drug efflux transporters P‐gp and multidrug resistance protein 1 (MRP1) were assessed by measuring the cellular uptake of 3H‐atazanavir or 3H‐ritonavir in P‐gp and MRP1 overexpressing cells as well as hCMEC/D3. Whereas the P‐gp inhibitor, PSC833, increased atazanavir and ritonavir accumulation in hCMEC/D3 cells by 2‐fold, the MRP inhibitor MK571 had no effect. P‐gp, MRP1, and hPXR expression and localization were examined by Western blot analysis and immunogold cytochemistry at the electron microscope level. Treatment of hCMEC/D3 cells for 72 hr with rifampin or SR12813 (two well‐established hPXR ligands) or PIs (atazanavir or ritonavir) resulted in an increase in P‐gp expression by 1.8‐, 6‐, and 2‐fold, respectively, with no effect observed for MRP1 expression. In hCMEC/D3 cells, cellular accumulation of these PIs appears to be primarily limited by P‐gp efflux activity. Long‐term exposure of atazanavir or ritonavir to brain microvessel endothelium may result in further limitations in brain drug permeability as a result of the up‐regulation of P‐gp expression and function. © 2008 Wiley‐Liss, Inc.</div></front></TEI><affiliations><list><country><li>Canada</li><li>France</li><li>Royaume-Uni</li><li>États-Unis</li></country><region><li>Ontario</li><li>Québec</li><li>État de New York</li><li>Île-de-France</li></region><settlement><li>Montréal</li><li>Paris</li><li>Toronto</li></settlement><orgName><li>Université de Toronto</li></orgName></list><tree><country name="Canada"><region name="Ontario"><name sortKey="Zastre, Jason A" sort="Zastre, Jason A" uniqKey="Zastre J" first="Jason A." last="Zastre">Jason A. Zastre</name></region><name sortKey="Bendayan, Moise" sort="Bendayan, Moise" uniqKey="Bendayan M" first="Moise" last="Bendayan">Moise Bendayan</name><name sortKey="Bendayan, Reina" sort="Bendayan, Reina" uniqKey="Bendayan R" first="Reina" last="Bendayan">Reina Bendayan</name><name sortKey="Bendayan, Reina" sort="Bendayan, Reina" uniqKey="Bendayan R" first="Reina" last="Bendayan">Reina Bendayan</name><name sortKey="Chan, Gary N Y" sort="Chan, Gary N Y" uniqKey="Chan G" first="Gary N. Y." last="Chan">Gary N. Y. Chan</name><name sortKey="Couraud, Pierre O" sort="Couraud, Pierre O" uniqKey="Couraud P" first="Pierre O." last="Couraud">Pierre O. Couraud</name><name sortKey="Ramaswamy, Manisha" sort="Ramaswamy, Manisha" uniqKey="Ramaswamy M" first="Manisha" last="Ramaswamy">Manisha Ramaswamy</name><name sortKey="Ronaldson, Patrick T" sort="Ronaldson, Patrick T" uniqKey="Ronaldson P" first="Patrick T." last="Ronaldson">Patrick T. Ronaldson</name></country><country name="France"><region name="Île-de-France"><name sortKey="Couraud, Pierre O" sort="Couraud, Pierre O" uniqKey="Couraud P" first="Pierre O." last="Couraud">Pierre O. Couraud</name></region><name sortKey="Couraud, Pierre O" sort="Couraud, Pierre O" uniqKey="Couraud P" first="Pierre O." last="Couraud">Pierre O. Couraud</name><name sortKey="Couraud, Pierre O" sort="Couraud, Pierre O" uniqKey="Couraud P" first="Pierre O." last="Couraud">Pierre O. Couraud</name><name sortKey="Couraud, Pierre O" sort="Couraud, Pierre O" uniqKey="Couraud P" first="Pierre O." last="Couraud">Pierre O. Couraud</name></country><country name="Royaume-Uni"><noRegion><name sortKey="Romero, Ignacio A" sort="Romero, Ignacio A" uniqKey="Romero I" first="Ignacio A." last="Romero">Ignacio A. Romero</name></noRegion></country><country name="États-Unis"><region name="État de New York"><name sortKey="Weksler, Babette" sort="Weksler, Babette" uniqKey="Weksler B" first="Babette" last="Weksler">Babette Weksler</name></region></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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