Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.6.3.44 (P-glycoprotein)
 13,344 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Penetrance of anti-retroviral drugs into the CNS depends partly on the activity of P-glycoprotein (P-gp), an ATP-dependent efflux pump involved in restricting entry of lipophilic drugs into the brain. The present study characterizes the patterns of P-gp expression in the brains of AIDS patients and examines its relationship with clinical and neuropathological indicators of HIV encephalitis (HIVE). For this purpose, brain tissue collected at autopsy from 26 subjects with a history of HIV (9 without HIVE; 17 with HIVE) was analyzed. Immunocytochemical staining and Western blot analyses for regional P-gp expression were performed and levels were correlated with neuropathological indicators and with HIV RNA. Double labeling experiments were performed with antibodies against astroglial (GFAP), endothelial (CD31), microglial (CD45) and neuronal (MAP2) cell markers. In the HIVE-negative cases, P-gp immunoreactivity was associated primarily with endothelial cells. HIVE-positive cases showed extensive immunolabeling of astroglial and microglial cells, but relatively less endothelial cell immunolabeling. No neuronal P-gp immunostaining was detected in brain tissue from any cases in the study. In the HIVE-positive cases with extensive astroglial labeling, the most intense immunoreactivity was detected in white matter. A subset of HIVE-positive cases displayed intense P-gp immunostaining of astrocytes closely associated with blood vessels in the cortex. Both the immunocytochemical and Western blot analyses showed a significant correlation between P-gp expression and HIV RNA levels. In conclusion, P-gp immunoreactivity was detected largely in glial cells in tissue from HIVE-positive patients. Furthermore, in HIVE-positive patients, brain viral burden and P-gp levels were significantly higher than those in HIVE-negative patients. Taken together, our data suggest that P-gp may be part of a central pathway mediating viral compartmentalization in the brains of HIV-infected individuals and may play a significant part in HIV disease progression in the brain.
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PMID:Altered P-glycoprotein expression in AIDS patients with HIV encephalitis. 1553 31

We examined the effects of two African herbal medicines recommended for HIV/AIDS patients on antiretroviral metabolism. Extracts from Hypoxis and Sutherlandia showed significant effects on cytochrome P450 3A4 metabolism and activated the pregnane X receptor approximately twofold. P-glycoprotein expression was inhibited, with Hypoxis showing 42-51% and Sutherlandia showing 19-31% of activity compared with verapamil. Initiating policies to provide herbal medicines with antiretroviral agents may put patients at risk of treatment failure, viral resistance or drug toxicity.
AIDS 2005 Jan 03
PMID:Impact of African herbal medicines on antiretroviral metabolism. 1562 40

Overexpression of P-glycoprotein (P-gp; ABCB1) can cause multidrug resistance during cancer and AIDS chemotherapy because of its ability to transport a broad range of structurally unrelated compounds from the cell. P-gp is a member of the ABC family of proteins. It is a single polypeptide containing four domains--two transmembrane (TM) domains each of which contains six TM segments, and two nucleotide-binding domains. Chemical modification and cross-linking studies of cysteine mutants of P-gp indicate that the common drug-binding pocket is at the interface between the TM domains. It has been postulated that drug substrates enter the lipid bilayer, are extracted by P-gp and transported to the extracellular medium. It is not clear how drug substrates enter the drug-binding pocket. Here, we propose that drug-substrates diffuse from the lipid bilayer into the drug-binding pocket through "gates" formed by TM segments at either end of the drug-binding pocket.
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PMID:Do drug substrates enter the common drug-binding pocket of P-glycoprotein through "gates"? 1573 3

Systemic disposition of antiviral drugs partly depends on renal handling of these compounds. There are some known, functionally characterized anionic and cationic transporters with varying substrate specificities for those drugs: human organic anion transporter (OAT) family (hOAT1-3) and human organic cation transporter (OCT) family (hOCT1-3), which mediate the intracellular flux, and adenosine 5'-triphosphate (ATP) binding cassette transporter family (P-glycoprotein, MRP2-5), which mediate the cellular efflux of antiviral drugs. The peptide transporter (PEPT1-2) mediate bi-directional facilitated diffusion of valacyclovir. All these transporters are expressed in the kidney. Organic anion and cation transporters primarily localize to the basolateral membrane of renal epithelial cells while ATP-binding cassette transporters primarily localize to the apical membrane. These transporters work in concert to mediate renal intracellular concentration of occurring antiviral drugs. Along with drug-metabolizing enzymes, these transporters are important determinants of drug effectiveness and toxicity. This review examines the role that these transporters play in renal disposition of antiviral drugs.
AIDS 2005 Mar 25
PMID:Renal tubular transporters and antiviral drugs: an update. 1576 50

The recent development of new antiretroviral drugs, along with the evolution in clinical practice guidelines that include the recommendation of the use of three- to four-drug combination regimens for achieving optimal suppression of viral replication, has focused clinicians on the relevance of drug-drug interactions in the chronic care of HIV-infected individuals. However, the routine clinical management of drug interactions is complicated by our expanding knowledge of the physiologic mechanisms underlying pharmacokinetic interactions, particularly as they relate to drug transport and tissue distribution (eg, P-glycoprotein) and biotransformation (hepatic cytochrome p450 mono-oxygenase induction and inhibition). This review provides an updated summary of key drug interactions that have been reported since its initial publication.
Curr HIV/AIDS Rep 2004 Jun
PMID:Drug interactions with antiretrovirals. 1609 Dec 28

Pharmacogenomic studies are contributing to our understanding of interindividual differences in response to antiretroviral drugs. Genetic polymorphism in major histocompatibility complex genes predict likelihood of hypersensitivity reactions in persons prescribed abacavir, and perhaps nevirapine. Recent studies have shown that a polymorphisms in the CYP2B6 gene is associated with higher plasma efavirenz concentrations and increased efavirenz central nervous system side effects. Polymorphisms in the MDR1 gene encoding the drug pump, P-glycoprotein, may predict nevirapine-associated hepatoxicity and long-term virologic response to efavirenz. CYP2C19 polymorphisms predict nelfinavir plasma levels and, possibly, risk of virologic failure on this drug. A European mitochondrial haplogroup may predict increased risk of peripheral neuropathy associated with nucleoside reverse transcriptase inhibitors. Expansion and refinement of knowledge regarding associations between human genetics and response to antiretroviral drugs may ultimately permit individualization of therapy based on genotyping. This article summarizes a presentation on HIV therapeutics and pharmacogenomics by David W. Haas, MD, at the International AIDS Society-USA course in Atlanta in March 2005.
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PMID:Will pharmacogenomic discoveries improve HIV therapeutics? 1617 Feb 25

In cancer and AIDS, overexpression of the MDR1 gene has important implications in the design of chemotherapy protocols because of the ability of its product, the ATP-dependent drug efflux pump P-glycoprotein (Pgp), to confer selective advantage to tumor and HIV-infected cells in the form of multidrug resistance. To study Pgp expression and physiology, we designed a translational fusion between the MDR1 and enhanced green fluorescent protein (EGFP) genes. The chimeric protein, Pgp-EGFP, was concentrated mainly in the plasma membrane and in the Golgi when expressed in drug-sensitive KB-3-1 cells. Doxorubicin, daunorubicin and rhodamine-123 efflux assays confirmed function of the chimeric pump. Also, at the single-cell level, an inverse relationship between Pgp-EGFP expression and nuclear doxorubicin accumulation was demonstrated. Polarized Pgp expression on the apical cell surface was confirmed by transfection of the MDR-EGFP fusion gene into MDCK cells. However, after colchicine selection, Pgp-EGFP was also detectable in the lateral domain of the transfected MDCK monolayers. These results indicate that drug selection affects not only expression, but cellular localization of Pgp. Furthermore, using a tet-based inducible expression system for Pgp-EGFP, we confirmed the stable nature of Pgp (t(1/2 total Pgp-EGFP) = 2.2 days), but revealed that surface-Pgp acquires extra stability as an active pump (t(1/2 surface Pgp-EGFP) = 3.7 days).
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PMID:An MDR-EGFP gene fusion allows for direct cellular localization, function and stability assessment of P-glycoprotein. 1630 69

Multidrug resistance (MDR) is a challenge in cancer treatment. One of the most studied mechanisms is P-glycoprotein (P-gp), which acts as a drug efflux pump, with decreased intracellular accumulation of drugs. It still needs to be clarified whether P-gp expression has a significant impact on non-Hodgkin's lymphoma treatment response, but a poor outcome has been reported in patients with positive P-gp expression. AIDS-related lymphomas have aggressive behavior, and although a complete response could be achieved, relapse is not uncommon. In an attempt to determine a possible relationship between MDR and poor outcome in this population, histologic samples obtained from 45 non-Hodgkin's lymphoma HIV-infected patients without previous cytotoxic therapy were submitted to immunohistochemical analysis using monoclonal antibody C494 specific for the MDR-1 isoform of P-gp. Samples from 27 patients (60%) were positive. Response to treatment (P=0.02) and overall survival (P=0.001) were significantly lower in patients with positive P-gp expression. In patients having achieved complete remission, the median disease-free survival (DFS) was not reached; the mean DFS was 57.2 months with DFS rates of 72.9% in three years. Our results show that P-gp is expressed before treatment of non-Hodgkin's lymphoma of HIV patients, and is related to poor response to treatment and overall survival.
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PMID:P-glycoprotein expression in non-Hodgkin's lymphomas of human immunodeficiency virus infected patients. 1715 97

P-glycoprotein (P-gp) can compromise the antiretroviral effect of a protease inhibitor (PI)-containing regimen for HIV-1, but can also reduce HIV-1 replication. We studied the net effect of P-gp on the intracellular HIV-1 RNA and DNA load in vivo. CD4(+) T cells were isolated from 27 HIV-1 patients (13 without and 14 with a PI-containing regimen) and subsequently sorted in CD45RO(-) (naive) and CD45RO(+) (memory) subsets with either high (P-gp(high)) or low (P-gp(low)) P-gp activity. Unspliced HIV-1 RNA and HIV-1 DNA load were determined. For each patient P-gp(high) and P-gp(low) subsets were compared. In patients on a PI-containing regimen, intracellular unspliced HIV-1 RNA was significantly lower in P-gp(high)-naive CD4(+) cells compared to P-gp(low)-naive CD4(+) cells (p = 0.04). The same trend was seen in naive CD4(+) cells of treatment naive patients. In both treated and untreated patients HIV-1 DNA levels were significantly lower in P-gp(high) than in P-gp(low) memory CD4(+) cells (p = 0.02 and p = 0.04). High cellular P-gp activity coincided with a reduced intracellular HIV-1 load in vivo, both in therapy-naive and in PI-treated patients. Therefore we conclude that the potential efflux function of P-gp on PIs may be clinically less relevant than the effect of P-gp on intracellular HIV-1 replication.
AIDS Res Hum Retroviruses 2007 Jan
PMID:Antiviral activity of HIV type 1 protease inhibitors nelfinavir and indinavir in vivo is not influenced by P-glycoprotein activity on CD4+ T cells. 1726 28

Extended treatment with human immunodeficiency virus (HIV) protease inhibitors (HPIs) is standard in HIV/AIDS therapy. While these drugs have helped decrease the overall incidence of AIDS defining illnesses, the relative prevalence of HIV/AIDS dementia has increased. HPIs may cause induction of blood-brain barrier (BBB) drug transporters (P-glycoprotein; P-gp) and thereby limit entry of HPIs into brain tissue, increasing the probability that the brain could become an HIV sanctuary site. Using bovine brain microvessel endothelial cells (BMEC) as an in-vitro model of the BBB, the potential for the HIV protease inhibitor ritonavir to cause induction of P-gp activity and expression was examined. BMEC were isolated from fresh cow brain by enzymatic digest and density centrifugation. Primary culture BMEC were co-incubated with ritonavir or vehicle control for 120 h. Quantitative drug accumulation of rhodamine 123 (Rh123) and fluorescence microscopy were used as measures of P-gp activity. P-gp expression was assessed using quantitative Western blotting. Ritonavir decreased Rh123 cell accumulation and increased P-gp immunoreactive protein in a concentration-dependent manner. Fluorescent microscopy mirrored Rh123 quantitative studies. In BMEC pretreated with 30 microM ritonavir, Rh123 accumulation was decreased 40% and immunoreactive P-gp protein increased 2-fold. Collectively, a strong correlation between decreased Rh123 BMEC accumulation and increased P-gp immunoreactive protein was observed (Spearman r2 = 0.77, P < 0.0001). Thus extended exposure of BMEC to ritonavir caused a concentration-dependent increase in P-gp activity and expression. Similar findings may occur at the clinical level with prolonged HIV protease inhibitor use, giving insight into the central nervous system as an HIV sanctuary site and eventual development of HIV dementia.
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PMID:Induction of P-glycoprotein expression and activity by ritonavir in bovine brain microvessel endothelial cells. 1763 89


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