title: Antiretroviral drug transporters and metabolic enzymes in human testicular tissue: potential contribution to HIV-1 sanctuary site.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Canada.
authors.forename: Yiying
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Canada.
authors.forename: Md Tozammel
authors.initials: MT
authors.lastname: Hoque
authors.affiliation: Department of Biological Sciences, Université du Québec à Montréal (UQAM), Montréal, Canada.
authors.forename: Mohammad-Ali
authors.initials: MA
authors.lastname: Jenabian
authors.affiliation: Chronic Viral Illness Service, McGill University Health Centre, Montréal, Canada.
authors.forename: Kishanda
authors.initials: K
authors.lastname: Vyboh
authors.affiliation: Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Canada.
authors.forename: Sana-Kay
authors.initials: SK
authors.lastname: Whyte
authors.affiliation: Faculty of Pharmacy, Université de Montréal, Montréal, Canada.
authors.forename: Nancy L
authors.initials: NL
authors.lastname: Sheehan
authors.affiliation: Metropolitan Centre of Plastic Surgery, Montréal, Canada.
authors.forename: Pierre
authors.initials: P
authors.lastname: Brassard
authors.affiliation: Metropolitan Centre of Plastic Surgery, Montréal, Canada.
authors.forename: Maud
authors.initials: M
authors.lastname: Bélanger
authors.affiliation: University of Montréal Hospital Research Centre, Montréal, Canada.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Chomont
authors.affiliation: Antiviral Pharmacology Laboratory, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: Courtney V
authors.initials: CV
authors.lastname: Fletcher
authors.affiliation: Chronic Viral Illness Service, McGill University Health Centre, Montréal, Canada.
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Routy
authors.affiliation: Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Canada r.bendayan@utoronto.ca.
authors.forename: Reina
authors.initials: R
authors.lastname: Bendayan
mesh_terms: D000328:Adult; D044966:Anti-Retroviral Agents / Q000378:metabolism* / Q000493:pharmacokinetics*; D001711:Biotransformation; D002853:Chromatography, Liquid; D004798:Enzymes / Q000032:analysis*; D020869:Gene Expression Profiling; D006801:Humans; D008297:Male; D026901:Membrane Transport Proteins / Q000032:analysis*; D008875:Middle Aged; D010949:Plasma / Q000737:chemistry; D020543:Proteome / Q000032:analysis; D053719:Tandem Mass Spectrometry; D013737:Testis / Q000737:chemistry / Q000187:drug effects* / Q000201:enzymology*; D055815:Young Adult
chemical_list: D044966:Anti-Retroviral Agents; D004798:Enzymes; D026901:Membrane Transport Proteins; D020543:Proteome