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Drug Transporters at the Human Blood-Testis Barrier - PubMed

Review

Drug Transporters at the Human Blood-Testis Barrier

Raymond K Hau et al. Drug Metab Dispos. 2023 May.

Abstract

Transporters are involved in the movement of many physiologically important molecules across cell membranes and have a substantial impact on the pharmacological and toxicological effect of xenobiotics. Many transporters have been studied in the context of disposition to, or toxicity in, organs such as the kidney and liver; however, transporters in the testes are increasingly gaining recognition for their role in drug transport across the blood-testis barrier (BTB). The BTB is an epithelial membrane barrier formed by adjacent Sertoli cells (SCs) in the seminiferous tubules that form intercellular junctional complexes to protect developing germ cells from the external environment. Consequently, many charged or large polar molecules cannot cross this barrier without assistance from a transporter. SCs express a variety of drug uptake and efflux transporters to control the flux of endogenous and exogenous molecules across the BTB. Recent studies have identified several transport pathways in SCs that allow certain drugs to circumvent the human BTB. These pathways may exist in other species, such as rodents and nonhuman primates; however, there is (1) a lack of information on their expression and/or localization in these species, and (2) conflicting reports on localization of some transporters that have been evaluated in rodents compared with humans. This review outlines the current knowledge on the expression and localization of pharmacologically relevant drug transporters in human testes and calls attention to the insufficient and contradictory understanding of testicular transporters in other species that are commonly used in drug disposition and toxicity studies. SIGNIFICANCE STATEMENT: While the expression, localization, and function of many xenobiotic transporters have been studied in organs such as the kidney and liver, the characterization of transporters in the testes is scarce. This review summarizes the expression and localization of common pharmacologically-relevant transporters in human testes that have significant implications for the development of drugs that can cross the blood-testis barrier. Potential expression differences between humans and rodents highlighted here suggest rodents may be inappropriate for some testicular disposition and toxicity studies.

Copyright © 2023 by The American Society for Pharmacology and Experimental Therapeutics.

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Figures

Fig. 1.
Fig. 1.

Illustration of a seminiferous tubule cross-section and a drug transporter pathway to bypass the BTB. LCs and vascular endothelial cells (blood capillary) occupy the interstitial tissue around the seminiferous tubules. PMCs line the outer edge to provide structural stability and contractility for moving spermatids through the seminiferous tubule. Within the seminiferous tubule are SCs that form intercellular junctional complexes that comprise the physical component of the BTB. Spermatogonia lie along the basal membranes of SCs exposed to the basal compartment, where they undergo mitotic division into primary spermatocytes and migrate past the junctional complexes. Primary spermatocytes undergo meiotic division to form secondary spermatocytes that will divide again into spermatids, which all occur in the adluminal compartment. Drug transporters expressed at the basal and apicolateral membranes of SCs can form a transport pathway for drugs in the blood to circumvent the BTB. Figure created with BioRender.com.

Fig. 2.
Fig. 2.

Localization of drug transporters in human testes. Summary of the localization of pharmacologically relevant drug transporters and their directionality in SCs, PMCs, LCs, developing germ cells, and vascular endothelial cells (blood capillary) in human testes. Question marks (?) indicate unknown directionality (CNT2 and MATE1) due to lack of functional transport analysis. Asterisks (*) indicate transporters (OATPs) that are speculated to localize to both the basal and apicolateral membranes of SCs based on positive immunostaining in human tissues but lack functional analysis to confirm this observation. Figure created with BioRender.com.

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