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Transporter‐mediated mechanism of nucleoside penetration of the blood‐testis barrier
Author(s) -
Klein David Michael,
Evans Kristen K.,
Hardwick Rhian N,
Dantzler William H,
Wright Stephen H,
Cherrington Nathan J
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.1047.7
Subject(s) - blood–testis barrier , sertoli cell , nucleoside , microbiology and biotechnology , uridine , chemistry , nucleoside transporter , transporter , biology , biochemistry , endocrinology , rna , spermatogenesis , gene
The blood‐testis barrier (BTB) prevents the entry of many therapeutics into the lumen of the seminiferous tubules (STs) shielding semen from chemical exposure. The BTB is formed by tight junctions between Sertoli cells. One drug class of HIV therapeutics, nucleoside analogs (NSAs), can penetrate the BTB and be detected in the semen. The purpose of this study is to determine the mechanisms by which NSAs are transported across the BTB. Transport studies in isolated rodent STs using H 3 uridine (K t 89.72uM) as a model nucleoside substrate indicate that Sertoli cells take up nucleosides almost exclusively via equilibrative nucleoside transporter 1 (ENT1). The IC 50 for NBMPR, an ENT inhibitor, is 12.9 nM. These data correspond with immunohistochemical staining of rat testes showing ENT1 on the basolateral membrane, whereas ENT2 is on the apical membrane of Sertoli cells. This localization suggests that ENT1 acts as an uptake transporter and ENT2 may facilitate the efflux of NSAs into the lumen of STs. Uptake of didanosine, a commonly used NSA, in HEK293 cells can be blocked by ENT1 inhibition. Trans‐epithelial transport of uridine by primary rat Sertoli cells can also be blocked by NBMPR. These data indicate a novel ENT1 and 2‐dominant mechanism for the transepithelial transport of nucleoside analogs across the BTB. AI083927.