HIV-1 Alters Intestinal Expression of Drug Transporters and Metabolic Enzymes: Implications for Antiretroviral Drug Disposition
| Autor: | Sharon Walmsley, Satya Dandekar, M. Tozammel Hoque, Sumathi Sankaran-Walters, Reina Bendayan, Olena Kis |
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| Rok vydání: | 2016 |
| Předmět: |
Male
0301 basic medicine Microarray Abcg2 HIV Infections ATP-binding cassette transporter Pharmacology Subfamily G 2.1 Biological and endogenous factors ATP Binding Cassette Transporter Subfamily G Member 2 Cytochrome P-450 CYP3A Medicine Pharmacology (medical) Aetiology chemistry.chemical_classification biology Multidrug resistance-associated protein 2 Pharmacology and Pharmaceutical Sciences Middle Aged Immunohistochemistry Multidrug Resistance-Associated Protein 2 Infectious Diseases Real-time polymerase chain reaction Subfamily B 5.1 Pharmaceuticals Medical Microbiology 6.1 Pharmaceuticals HIV/AIDS Female Development of treatments and therapeutic interventions Multidrug Resistance-Associated Proteins Infection Member 2 Adult Member 1 ATP Binding Cassette Transporter Subfamily B Anti-HIV Agents ATP Binding Cassette Transporter Real-Time Polymerase Chain Reaction Microbiology 03 medical and health sciences Clinical Research Humans ATP Binding Cassette Transporter Subfamily B Member 1 CYP3A4 business.industry Prevention Evaluation of treatments and therapeutic interventions 030104 developmental biology Enzyme chemistry Immunology HIV-1 biology.protein Transcriptome business |
| Zdroj: | Antimicrobial agents and chemotherapy, vol 60, iss 5 |
| ISSN: | 1098-6596 0066-4804 |
| DOI: | 10.1128/aac.02278-15 |
| Popis: | This study investigated the effects of HIV-1 infection and antiretroviral therapy (ART) on the expression of intestinal drug efflux transporters, i.e., P-glycoprotein (Pgp), multidrug resistance-associated proteins (MRPs), and breast cancer resistance protein (BCRP), and metabolic enzymes, such as cytochrome P450s (CYPs), in the human upper intestinal tract. Intestinal biopsy specimens were obtained from HIV-negative healthy volunteers, ART-naive HIV-positive (HIV + ) subjects, and HIV + subjects receiving ART (10 in each group). Intestinal tissue expression of drug transporters and metabolic enzymes was examined by microarray, real-time quantitative reverse transcription-PCR (qPCR), and immunohistochemistry analyses. Microarray analysis demonstrated significantly lower expression of CYP3A4 and ABCC2 /MRP2 in the HIV + ART-naive group than in uninfected subjects. qPCR analysis confirmed significantly lower expression of ABCC2 /MRP2 in ART-naive subjects than in the control group, while CYP3A4 and ABCG2 /BCRP showed a trend toward decreased expression. Protein expression of MRP2 and BCRP was also significantly lower in the HIV + naive group than in the control group and was partially restored to baseline levels in HIV + subjects receiving ART. In contrast, gene and protein expression of ABCB1 /Pgp was significantly increased in HIV + subjects on ART relative to HIV + ART-naive subjects. These data demonstrate that the expression of drug-metabolizing enzymes and efflux transporters is significantly altered in therapy-naive HIV + subjects and in those receiving ART. Since CYP3A4, Pgp, MRPs, and BCRP metabolize or transport many antiretroviral drugs, their altered expression with HIV infection may negatively impact drug pharmacokinetics in HIV + subjects. This has clinical implications when using data from healthy volunteers to guide ART. |
| Databáze: | OpenAIRE |
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