Functional Expression of ABC Transporters at Blood-tissue Barriers: Relevance to Antiretroviral Drug Tissue Distribution
Notice bibliographique
Résumé
Although combination antiretroviral therapy is successful in reducing HIV-1 viral loads in plasma, several tissue compartments i.e., the brain and male genital tract have been identified as viral reservoirs which can harbor actively replicating HIV-1 virus (Chan, 2005;Dahl, et al., 2010;Smith, et al., 2007;Solas, et al., 2003). In addition to harboring the virus, several studies have observed antiretroviral drugs present at sub-therapeutic concentrations in these tissue compartments that may contribute to the formation of drug resistance and allow systemic viral repopulation. ATP-binding cassette drug efflux transporters i.e., P-glycoprotein and breast cancer resistance protein, have been previously shown to efflux antiretroviral drugs at the level of blood-brain barrier (Dallas, et al., 2004a;Lee, et al., 2007;Lee and Bendayan, 2004;Ronaldson, et al., 2004;Ronaldson, et al., 2007); however, few studies have examined the role of these transporters at the blood-testis barrier. The overall goal of this thesis was to investigate the functional expression of ATP-binding cassette drug efflux transporters at tissue-plasma barriers i.e., the blood-brain barrier and the blood-testis barrier, and provide insight into the role that these transporters play in limiting the distribution of antiretroviral drugs into these potential sanctuary tissues. We demonstrated that P-glycoprotein, breast cancer resistance protein and multidrug resistance associated protein-1 are localized and expressed at the plasma membrane in primary human Sertoli cells and mouse Sertoli cell culture systems using quantitative polymerase chain reaction, immunoblotting and confocal immunofluorescence microscopy, respectively. In mouse Sertoli cell culture systems, using radiolabeled and fluorescent substrates of P-glycoprotein, breast cancer resistance protein and multidrug resistance associated proteins; we demonstrated that these transporters are not only expressed, but also functional in this cell system. We observed that several of the antiretroviral drugs can serve as both, substrates and inhibitors of these transporters at clinically relevant concentrations, including several of the protease inhibitors. We further examined the role of drug transporters in the tissue distribution of atazanavir and observed that P-glycoprotein/breast cancer resistance protein (Mdr1a/1b-/-. Abcg2-/-) knockout mice and wild-type mice pre-treated with the P-glycoprotein and breast cancer resistance protein inhibitor, elacridar, have enhanced accumulation of atazanavir in brain and testes tissues compared to control mice. In addition, we investigated the role of ritonavir as a potential inhibitor of P-glycoprotein and breast cancer resistance protein, using Cyp3a-/- (8-gene) knockout mouse model, and demonstrated that ritonavir can modestly enhance the accumulation of atazanavir in the brain and testes tissues. To better understand the role of HIV-1 viral proteins on the mRNA expression of ATP-binding cassette drug efflux transporters, we examined their expression in a HIV-1 transgenic rat model, and showed that HIV-1 viral transgene expression can affect the expression of ATP-binding cassette drug efflux transporters in both a tissue- and age-dependent manner. The results from these studies have generated new information on the mechanisms of transport and distribution of antiretroviral drugs at the blood-testis barrier and the blood-brain barrier, and could better guide more effective antiretroviral therapy to reduce potential sexual transmission of HIV-1 and prevention of HIV-1 associated neurological complications.
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,001 | 0,001 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,001 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,001 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».