Drug transporters in spermatogenesis: A re-evaluation of recent data on P-glycoprotein

Abstract

Drug transporters are integral membrane proteins expressed by a variety of organs, including the liver, kidney, small intestine and testis, and they are generally known to mediate drug or xenobiotic transport into and out of cells. Previous studies have also reported the presence of several drug transporters at blood-tissue barriers where they are thought to protect organs from harmful agents. In this editorial, we briefly discuss and re-evaluate recent findings that show P-glycoprotein, an efflux pump, to function at the blood-testis barrier. We also put forth a mechanistic model, hoping this information will form a strong basis for future studies.

Figure 1. A mechanistic model of P-glycoprotein function at the BTB. Previous studies have shown P-glycoprotein to localize at the BTB and to co-immunoprecipitate with structural TJ proteins, namely occludin, claudin-11 and JAM-A, which assemble into a multi-protein complex via ZO-1 and FAK (see text for references). To better understand the role of P-glycoprotein at the BTB, Sertoli cells were isolated from testes of 20 d old rats and cultured at high density on Matrigel-coated substrata for 3–4 d to allow the assembly of a functional Sertoli cell barrier. Thereafter, Mdr1 was silenced by RNAi (denoted by an “X”), and barrier function was assessed by transepithelial electrical resistance measurements, immunoblotting and immunolocalization experiments. Following knockdown, Sertoli cell barrier dysfunction was noted. Specifically, the association between occludin and ZO-1 was disrupted (denoted by connected lines that end with an “X”), which increased the association between occludin and FAK. This resulted in the Thr phosphorylation (denoted by an encircled “P”) and in the endocytosis (denoted by a large circle) of occludin, disrupting the integrity of TJs. A decrease in the steady-state level of claudin-11 (denoted by a dotted-line) was also observed, contributing to TJ dysfunction as well. BTB dysfunction resulting from the loss of P-glycoprotein may also allow entry of drugs, toxicants and steroids (denoted by an assortment of symbols), which would have otherwise been prohibited from entering or pumped out in the presence of P-glycoprotein at the BTB. An additional study has reported P-glycoprotein to associate with actin via the ezrin-radixin and moesin (ERM) protein complex, but it is not known if this findings applies to the testis as well. Future experiments are also needed to identify the mechanism behind the decrease in claudin-11 following knockdown of Mdr1. For simplicity, other junction types that contribute to BTB function have been omitted, and only selected TJ proteins have been included.