Abstract
Poor antiretroviral drug (ARV) penetration in the testes could be due, in part, to the presence of ATP-binding cassette (ABC) membrane–associated drug efflux transporters such as P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and multidrug resistance–associated proteins (MRPs) expressed at the blood-testis barrier (BTB). The functional expression of these transporters is known to be regulated by ligand-activated nuclear receptors pregnane X receptor (PXR) and constitutive androstane receptor (CAR) in various tissues. This study aimed to investigate in vitro and ex vivo the role of PXR and CAR in the regulation of ABC transporters at the BTB. Both PXR and CAR proteins were expressed in human testicular tissue and in mouse TM4 Sertoli cells (an in vitro cell line model of the BTB). In addition, we demonstrated an upregulation of P-gp, Bcrp, and Mrp4 mRNA and protein expression, after exposure to PXR or CAR ligands in TM4 cells. Small interfering RNA downregulation of PXR or CAR attenuated the expression of these transporters, suggesting the direct involvement of these nuclear receptors in regulating P-gp, Bcrp, and Mrp4 in this system. In an ex vivo study using freshly isolated mouse seminiferous tubules, we found that exposure to PXR or CAR ligands, including ARVs, significantly increased P-gp expression and function. Together, our data suggest that ABC transporters could be regulated at the BTB during chronic treatment with ARVs that can serve as ligands for PXR and CAR, which could in turn further limit testicular ARV concentrations.
Footnotes
- Received June 28, 2017.
- Accepted September 14, 2017.
This work was supported by the University of Toronto [Leslie Dan Faculty of Pharmacy Internal Grant 923465 (to R.B.)] and by the Canadian Institutes of Health Research [Catalyst Operating Grant 296635 and Canadian HIV Cure Enterprise Team Grant HIG-133050 (to J.-P.R., M.-A.J., and R.B.)] in partnership with the Canadian Foundation for AIDS Research and the 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 Scholarship for Doctoral Students. M.A.J. holds the Canada Research Chair Tier 2 in Immuno-Virology.
↵This article has supplemental material available at jpet.aspetjournals.org.
- Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics
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