Antiretroviral drug transporters and metabolic enzymes in human testicular tissue: potential contribution to HIV-1 sanctuary site
| العنوان: | Antiretroviral drug transporters and metabolic enzymes in human testicular tissue: potential contribution to HIV-1 sanctuary site |
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| المؤلفون: | Mohammad-Ali Jenabian, Nicolas Chomont, Courtney V. Fletcher, Md. Tozammel Hoque, Sana-Kay Whyte, Kishanda Vyboh, Nancy L. Sheehan, Pierre Brassard, Yiying Huang, Maud Bélanger, Reina Bendayan, Jean-Pierre Routy |
| المصدر: | Journal of Antimicrobial Chemotherapy. 71:1954-1965 |
| بيانات النشر: | Oxford University Press (OUP), 2016. |
| سنة النشر: | 2016 |
| مصطلحات موضوعية: | Adult, Male, 0301 basic medicine, Microbiology (medical), Proteome, Abcg2, Organic anion transporter 1, Equilibrative nucleoside transporter 2, Pharmacology, Concentrative nucleoside transporter, Plasma, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Tandem Mass Spectrometry, Testis, Constitutive androstane receptor, Humans, Pharmacology (medical), Receptor, Biotransformation, Original Research, Pregnane X receptor, biology, Gene Expression Profiling, Membrane Transport Proteins, Middle Aged, Enzymes, 3. Good health, Solute carrier family, 030104 developmental biology, Infectious Diseases, Anti-Retroviral Agents, Biochemistry, biology.protein, 030217 neurology & neurosurgery, Chromatography, Liquid |
| الوصف: | OBJECTIVES The testes are a potential viral sanctuary site for HIV-1 infection. Our study aims to provide insight into the expression and localization of key drug transporters and metabolic enzymes relevant to ART in this tissue compartment. METHODS We characterized gene and protein expression of 12 representative drug transporters and two metabolic enzymes in testicular tissue samples obtained from uninfected (n = 8) and virally suppressed HIV-1-infected subjects on ART (n = 5) and quantified antiretroviral drug concentrations in plasma and testicular tissues using LC/MS/MS from HIV-1-infected subjects. RESULTS Our data demonstrate that key ABC drug transporters (permeability glycoprotein, multidrug-resistance protein 1, 2 and 4, and breast cancer resistance protein), solute carrier transporters (organic anion transporting polypeptides 1B1 and 2B1, organic anion transporter 1, concentrative nucleoside transporter 1, equilibrative nucleoside transporter 2) and cytochrome P450 metabolic enzymes (CYP3A4 and CYP2D6) previously shown to interact with many commonly used antiretroviral drugs are expressed at the mRNA and protein level in the testes of both subject groups and localize primarily at the blood-testis barrier, with no significant differences between the two groups. Furthermore, we observed that PIs known to be substrates for ATP-binding cassette membrane transporters, displayed variable testicular tissue penetration, with darunavir concentrations falling below therapeutic values. In contrast, the NRTIs emtricitabine, lamivudine and tenofovir displayed favourable tissue penetration, reaching concentrations comparable to plasma levels. We also demonstrated that nuclear receptors, peroxisome proliferator-activated receptors α and γ exhibited higher gene expression in the testicular tissue compared with pregnane X receptor and constitutive androstane receptor, suggesting a potential regulatory pathway governing drug transporter and metabolic enzyme expression in this tissue compartment. CONCLUSIONS Our data suggest the testes are a complex pharmacological compartment that can restrict the distribution of certain antiretroviral drugs and potentially contribute to HIV-1 persistence. |
| تدمد: | 1460-2091 0305-7453 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::408b0909c49179d3ac014ca8289ab816Test https://doi.org/10.1093/jac/dkw046Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....408b0909c49179d3ac014ca8289ab816 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 14602091 03057453 |
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