Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.23.16 (HIV-1 protease)
 2,107 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Transport by ATP-dependent efflux pumps such as P-glycoprotein is an increasingly recognized determinant of drug disposition. P-glycoprotein does not only contribute to multidrug resistance (MDR) in tumor cells, it is also expressed in normal tissues with excretory function such as liver, kidney and intestine. Apical expression of P-glycoprotein in such tissues results in reduced drug absorption from the gastrointestinal tract and enhanced drug elimination into bile and urine. Moreover, expression of P-glycoprotein in the endothelial cells of the blood-brain barrier prevents entry of certain drugs into the central nervous system. Human P-glycoprotein has been shown to transport a wide range of structurally unrelated drugs such as digoxin, quinidine, cyclosporine and HIV-1 protease inhibitors. Drug administration to P-glycoprotein knock-out and control mice provided data on the importance of P-glycoprotein for absorption after oral administration and penetration through the blood-brain barrier. Moreover, P-glycoprotein knock-out mice were used to identify inhibition of P-glycoprotein-mediated transport as a mechanism for drug interactions such as the digoxin-quinidine interaction. Studies in humans indicate a particular importance of intestinal P-glycoprotein for bioavailability of the immunosuppressant cyclosporine. Moreover, induction of intestinal P-glycoprotein by rifampin has now been identified as the major underlying mechanism of reduced digoxin plasma concentrations during concomitant rifampin therapy. In summary, P-glycoprotein functions as a defense mechanism, which determines bioavailability and CNS concentrations of drugs. Modification of P-glycoprotein function is an important underlying mechanism of drug interactions in humans. However, disposition of a drug and its metabolites frequently is not only determined by P-glycoprotein, but also by drug-metabolizing enzymes and possibly by drug transporters other than P-glycoprotein [e.g. members of the MRP family (MRP = multidrug resistance-associated proteins)].
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PMID:P-glycoprotein: a defense mechanism limiting oral bioavailability and CNS accumulation of drugs. 1070 93

The constituents of highly active anti-retroviral therapy (HAART) include HIV-1 protease inhibitors (HPIs) and nucleoside reverse transcriptase inhibitors (NRTIs). Endothelial cell (EC) barriers, especially the blood-brain-barrier (BBB) suppresses the entry of HAART drugs to subendothelial HIV-1 reservoirs. The ATP binding cassette (ABC) transporter family members, multidrug resistant-1 (MDR-1) and multidrug resistance-associated proteins (MRPs) can efflux both HPIs and NRTIs from intracellular compartments. Using brain derived ECs from non-human sources, previous studies suggested a dominant role for MDR-1 in HAART efflux from the BBB. However, due to species variations in ABC-transporter expression, drug-efflux functions using human brain ECs need to be investigated. Furthermore, roles of ABC-transporters in drug-efflux from systemic EC barriers need to be studied. We monitored the expression of ABC-transporters in primary human ECs obtained from brain (HBMVECs), aorta (HAECs), pulmonary-artery (HPAECs), dermal-microvessel (HDMVECs) and umbilical vein (HUVECs). Gene expression for MDR-1 and MRPs (MRP-1 to MRP-5) were analyzed by reverse transcriptase polymerase chain reaction (RT-PCR). Drug efflux functions were determined by calcein retention assays. Intracellular accumulation of both 3H-saquinavir (an HPI) and 3H-zidovudine (an NRTI) were also monitored in HAECs and HBMVECs. Both assays were carried out in presence of verapamil (20-60 microM) or MK-571 (12.5-50 microM) inhibitors of MDR-1 and MRPs, respectively in presence of verapamil or MK-571. The HBMVECs expressed higher levels of MRPs than MDR-1 and only MK-571 significantly (P<0.01) suppressed calcein efflux from these cells. However, both HAECs and HPAECs showed MDR-1 and MRP expression and calcein efflux was inhibited by both verapamil and MK-571. Both inhibitors suppressed 3H-saqubinavir efflux from HAECs, but only MK-571 suppressed saquinavir efflux from HBMVECs. In both ECs, 3H-zidovudine efflux was only suppressed by MK-571. Thus, primary human ECs, especially brain derived ECs, predominantly express MRPs and their specific inhibition may enhance HAART efficacy in subendothelial HIV-1 reservoirs.
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PMID:MRP (ABCC) transporters-mediated efflux of anti-HIV drugs, saquinavir and zidovudine, from human endothelial cells. 1853 59

The highly active anti-retroviral therapy (HAART) regimen has considerably reduced the mortality rate in HIV-1 positive patients. However, long-term exposure to HAART is associated with a metabolic syndrome manifesting cardiovascular dysfunction, lipodystrophy, and insulin resistance syndrome (IRS). The inclusion of HIV-1 protease inhibitors (PIs) in HAART has been linked to the induction of IRS. Although several molecular mechanisms of PI-induced effects on insulin action have been postulated, the deleterious effects of PIs on insulin production by pancreatic beta-cells have not been fully investigated and therapeutic strategies to ameliorate insulin dysregulation at this level have not been targeted. The present study showed that exposure to several different PIs, nelfinavir (5-10 microM), saquinavir (5-10 microM) and atazanavir (8-20 microM), decreases glucose stimulated insulin secretion from rat pancreatic beta-cells (INS-1). Nelfinavir significantly increased reactive oxygen species (ROS) generation and suppressed cytosolic, but not mitochondrial superoxide dismutase (SOD) levels. Nelfinvair also decreased both glutathione and ATP and increased UCP2 levels in these cells. Simultaneous treatment with thymoquinone (TQ) (2.5 microM), an active ingredient of black seed oil, significantly inhibited the effect of nelfinavir on augmented ROS production and suppressed SOD levels. Both TQ and black seed oil exposure increased glucose stimulated insulin secretion and ameliorated the suppressive effect of nelfinavir. The present findings imply a direct role of ROS in PI induced deleterious effects on pancreatic beta-cells. Our findings also suggest that TQ may be used as a potential therapeutic agent to normalize the dysregulated insulin production observed in HAART treated patients.
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PMID:HIV-1 protease inhibitor induced oxidative stress suppresses glucose stimulated insulin release: protection with thymoquinone. 1933 53

Persistence of HIV-1 reservoirs within the Central Nervous System (CNS) remains a significant challenge to the efficacy of potent anti-HIV-1 drugs. The primary human Brain Microvascular Endothelial Cells (HBMVEC) constitutes the Blood Brain Barrier (BBB) which interferes with anti-HIV drug delivery into the CNS. The ATP binding cassette (ABC) transporters expressed on HBMVEC can efflux HIV-1 protease inhibitors (HPI), enabling the persistence of HIV-1 in CNS. Constitutive low level expression of several ABC-transporters, such as MDR1 (a.k.a. P-gp) and MRPs are documented in HBMVEC. Although it is recognized that inflammatory cytokines and exposure to xenobiotic drug substrates (e.g HPI) can augment the expression of these transporters, it is not known whether concomitant exposure to virus and anti-retroviral drugs can increase drug-efflux functions in HBMVEC. Our in vitro studies showed that exposure of HBMVEC to HIV-1 significantly up-regulates both MDR1 gene expression and protein levels; however, no significant increases in either MRP-1 or MRP-2 were observed. Furthermore, calcein-AM dye-efflux assays using HBMVEC showed that, compared to virus exposure alone, the MDR1 mediated drug-efflux function was significantly induced following concomitant exposure to both HIV-1 and saquinavir (SQV). This increase in MDR1 mediated drug-efflux was further substantiated via increased intracellular retention of radiolabeled [(3)H-] SQV. The crucial role of MDR1 in (3)H-SQV efflux from HBMVEC was further confirmed by using both a MDR1 specific blocker (PSC-833) and MDR1 specific siRNAs. Therefore, MDR1 specific drug-efflux function increases in HBMVEC following co-exposure to HIV-1 and SQV which can reduce the penetration of HPIs into the infected brain reservoirs of HIV-1. A targeted suppression of MDR1 in the BBB may thus provide a novel strategy to suppress residual viral replication in the CNS, by augmenting the therapeutic efficacy of HAART drugs.
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PMID:Specific increase in MDR1 mediated drug-efflux in human brain endothelial cells following co-exposure to HIV-1 and saquinavir. 2409 80