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Xenobiotic Nuclear Receptors Pregnane X Receptor and Constitutive Androstane Receptor Regulate Antiretroviral Drug Efflux Transporters at the Blood-Testis Barrier S

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Xenobiotic Nuclear Receptors Pregnane X Receptor and Constitutive Androstane Receptor Regulate Antiretroviral Drug Efflux Transporters at the Blood-Testis Barrier S Supplemental material to this article can be found at: http://jpet.aspetjournals.org/content/suppl/2017/09/28/jpet.117.243584.DC1 1521-0103/363/3/324–335$25.00 https://doi.org/10.1124/jpet.117.243584 THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS J Pharmacol Exp Ther 363:324–335, December 2017 Copyright ª 2017 by The American Society for Pharmacology and Experimental Therapeutics Xenobiotic Nuclear Receptors Pregnane X Receptor and Constitutive Androstane Receptor Regulate Antiretroviral Drug Efflux Transporters at the Blood-Testis Barrier s Sana-Kay Whyte-Allman, Md Tozammel Hoque, Mohammad-Ali Jenabian, Jean-Pierre Routy, and Reina Bendayan Graduate Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada (S.-K.W.-A., M.T.H., R.B.); Department of Biological Sciences, Université du Québec à Montréal, Montréal, Quebec, Canada (M.-A.J.); and Chronic Viral Illness Service, McGill University Health Centre, Montréal, Quebec, Canada (J.-P.R.) Downloaded from Received June 28, 2017; accepted September 14, 2017 ABSTRACT Poor antiretroviral drug (ARV) penetration in the testes could addition, we demonstrated an upregulation of P-gp, Bcrp, and be due, in part, to the presence of ATP-binding cassette Mrp4 mRNA and protein expression, after exposure to PXR or (ABC) membrane–associated drug efflux transporters such as CAR ligands in TM4 cells. Small interfering RNA downregulation jpet.aspetjournals.org P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), of PXR or CAR attenuated the expression of these transporters, and multidrug resistance–associated proteins (MRPs) expressed suggesting the direct involvement of these nuclear receptors in at the blood-testis barrier (BTB). The functional expression of regulating P-gp, Bcrp, and Mrp4 in this system. In an ex vivo these transporters is known to be regulated by ligand-activated study using freshly isolated mouse seminiferous tubules, we nuclear receptors pregnane X receptor (PXR) and constitutive found that exposure to PXR or CAR ligands, including ARVs, androstane receptor (CAR) in various tissues. This study aimed significantly increased P-gp expression and function. Together, to investigate in vitro and ex vivo the role of PXR and CAR in our data suggest that ABC transporters could be regulated at the regulation of ABC transporters at the BTB. Both PXR and the BTB during chronic treatment with ARVs that can serve at ASPET Journals on September 24, 2021 CAR proteins were expressed in human testicular tissue and in as ligands for PXR and CAR, which could in turn further mouse TM4 Sertoli cells (an in vitro cell line model of the BTB). In limit testicular ARV concentrations. Introduction the testis could, in part, restrict ARV concentrations in the seminal fluid of HIV-infected men (Else et al., 2011). The testis Despite the use of highly active antiretroviral therapy, is an immunoprivileged environment where the blood-testis human immunodeficiency virus (HIV)-1 persistence in ana- barrier (BTB), due to its physical and biochemical properties, tomic reservoirs and sanctuary sites such as the lymph nodes, can limit the penetration of exogenous agents into this tissue. brain, and testes can be attributed, in part, to the low This barrier is primarily composed of adjacent epithelial antiretroviral drug (ARV) concentrations reached in these Sertoli cells, which form tight junction complexes near the tissues (Dahl et al., 2010; Fletcher et al., 2014; Huang et al., basement membrane and physically divide the seminiferous 2016; Jenabian et al., 2016). Semen is the most common vector epithelium into apical and basolateral compartments. This for HIV transmission globally and limited ARV penetration in allows for spermatid development in a microenvironment within the seminiferous tubules where the entrance of anti- sperm antibodies and harmful xenobiotics is restricted (Su This work was supported by the University of Toronto [Leslie Dan Faculty of et al., 2011). Pharmacy Internal Grant 923465 (to R.B.)] and by the Canadian Institutes of Health Research [Catalyst Operating Grant 296635 and Canadian HIV Cure ARV disposition in rodents and humans primarily involves Enterprise Team Grant HIG-133050 (to J.-P.R., M.-A.J., and R.B.)] in intracellular drug metabolism and transport by members of partnership with the Canadian Foundation for AIDS Research and the the ATP-binding cassette (ABC) and solute carrier (SLC) International AIDS Society. R.B. is a career scientist of the Ontario HIV Treatment Network. S.-K.W.-A. is a recipient of the Connaught International superfamilies of drug transport proteins across biologic mem- Scholarship for Doctoral Students. M.A.J. holds the Canada Research Chair branes. The ABC family includes several drug efflux trans- Tier 2 in Immuno-Virology. doi.org/10.1124/jpet.117.243584. porters such as P-glycoprotein (P-gp; ABCB1), multidrug s This article has supplemental material available at jpet.aspetjournals.org. resistance–associated proteins (MRPs; ABCC), and breast ABBREVIATIONS: ABC, ATP-binding cassette; ARV, antiretroviral drug; BBB, blood-brain barrier; BCRP, breast cancer resistance protein; BTB, blood- testis barrier; CAR, constitutive androstane receptor; CsA, cyclosporine A; DMEM, Dulbecco’s modified Eagle’s medium; DMSO, dimethylsulfoxide; GR, glucocorticoid receptor; HEK, human embryonic kidney; HIV, human immunodeficiency virus; MRP, multidrug resistance–associated protein; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; P-gp, P-glycoprotein; PCN, pregnenolone 16a carbonitrile; PI, protease inhibitor; PSC833, 6-[(2S,4R,6E)-4-methyl-2-(methylamino)-3-oxo-6-octenoic acid]-7-L-valine-cyclosporin A; PXR, pregnane X receptor; qPCR, quantitative real- time polymerase chain reaction; siRNA, small interfering RNA; SLC, solute carrier; TCPOBOP, 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene. 324 Regulation of ABC Transporters in the Testis 325 cancer resistance protein (BCRP; ABCG2), whereas the SLC purchased from Moravek Biochemicals (Brea, CA). Valspodar transporters comprise organic anion-transporting polypep- (PSC833; 6-[(2S,4R,6E)-4-methyl-2-(methylamino)-3-oxo-6-octenoic tides, organic anion and organic cation transporters, and acid]-7-L-valine-cyclosporin A) was a generous gift from Novartis equilibrative and concentrative nucleoside transporters (Kis Pharma (Basel, Switzerland). Cyclosporine (CsA) was obtained from et al., 2010). Our group and others have demonstrated in vitro Tocris Biosciences (Ellisville, MO). 1,4-Bis[2-(3,5-dichloropyridyloxy)] benzene (TCPOBOP), dexamethasone, ketoconazole, and 3-(4,5- and in vivo that several efflux transporters are functionally dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) were expressed at the BTB and could potentially limit the penetra- purchased from Sigma-Aldrich (Oakville, ON, Canada). Pregnenolone tion of ARVs into rodent and human testes (Choo et al., 2000; 16a carbonitrile (PCN) was purchased from Cayman Chemicals (Ann Robillard et al., 2012, 2014; Huang et al., 2016). Arbor, MI). Type I collagen was purchased from BD Biosciences Most ARVs from the protease inhibitor (PI) class are known to (San Jose, CA). Small interfering RNA (siRNA) against mouse PXR be substrates of P-gp, whereas BCRP is primarily involved in the (sc-44058), CAR (sc-43663), and glucocorticoid receptor (GR) (sc-35506) transport of several of the nucleoside and non-nucleoside reverse and nonsilencing negative control siRNA (sc-37007) were purchased transcriptase inhibitors. Both P-gp and BCRP have also been from Santa Cruz Biotechnology (Santa Cruz, CA). Each siRNA product implicated in the efflux of integrase strand transfer inhibitor contained a pool of three target-specific 19- to 25-nt siRNAs designed to drugs such as dolutegravir and raltegravir. The MRP isoforms knock down gene expression. The mouse anti-actin, goat anti-PXR, rabbit anti-CAR, and rabbit anti-GR antibodies were also obtained are also known to be involved in the transport of ARVs. In from Santa Cruz Biotechnology Inc. Please note that the rabbit anti- particular, MRP4 is involved in the efflux of several nucleoside CAR (sc-13065) antibody obtained from Santa Cruz Biotechnology has Downloaded from reverse transcriptase inhibitors such as lamivudine, tenofovir, been reported by the company to identify CAR at around 55–60 kDa. In and abacavir. In addition to being substrates, many ARVs also addition, several groups including ours have detected CAR at around interact with these transporters as inducers and/or inhibitors 50–60 kDa using this antibody (Hernandez et al., 2009; Wang et al., (Supplemental Table 1). Recently, we characterized the expres- 2010; Chan et al., 2011), even though the predicted molecular weight of sion and localization of drug transporters and metabolic en- CAR has been reported at around 40–45 kDa based on its amino acid zymes involved in ARV transport in the testes of HIV-infected sequence. This potentially could be due to changes in the phosphory- individuals receiving ARV therapy and we measured plasma lation of the molecule (Mutoh et al., 2009) or to other post-translational jpet.aspetjournals.org and testicular drug concentrations. In particular, darunavir, a modifications that could affect the migration of the protein in different tissues. Mouse anti–P-gp antibody, rat anti-Bcrp antibody, and rat anti- P-gp substrate that is currently recommended as a preferred PI Mrp4 antibody were purchased from Enzo Life Sciences (Farmingdale, regimen
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