Organic Anion Transporter 6 (Slc22a20) Specificity and Sertoli Cell-Specific Expression Provide New Insight on Potential Endogenous Roles
Document Type
Article
Original Publication Date
2010
Journal/Book/Conference Title
Journal of Pharmacology and Experimental Therapeutics
Volume
334
Issue
3
First Page
927
Last Page
935
DOI of Original Publication
10.1124/jpet.110.168765
Date of Submission
October 2015
Abstract
Organic anion transporter 6 (Oat6; Slc22a20), a member of the OAT family, was demonstrated previously to mediate the transport of organic anions (Am J Physiol Renal Physiol 291:F314–F321, 2006). In the present study, we sought to further delineate the function of murine Oat6 (mOat6) by analyzing the effect of select organic anions on mOat6-mediated transport by using a Chinese hamster ovary (CHO) cell line stably expressing mOat6 (CHO-mOat6). When examined, kinetic analysis demonstrated that the mechanism of inhibition of mOat6 and mOat3 was competitive. Homovanillic acid, 5-hydroxyindole acetic acid, 2,4-dihydroxyphenylacetate, hippurate, and dehydroepiandrosterone sulfate (DHEAS) each significantly reduced mOat6 activity with inhibitory constant (Ki) values of 3.0 ± 0.5, 48.9 ± 10.3, 61.4 ± 7.1, 59.9 ± 4.9, and 38.8 ± 3.1 μM, respectively. Comparison to Ki values determined for mOat3 (67.8 ± 7.2, 134.5 ± 27.0, 346.7 ± 97.9, 79.3 ± 4.0, and 3.8 ± 1.1 μM, respectively) revealed that there are significant differences in compound affinity between each transporter. Fluoroquinolone antimicrobials and reduced folates were without effect on mOat6-mediated uptake. Investigation of testicular cell type-specific expression of mOat6 by laser capture microdissection and quantitative polymerase chain reaction revealed significant mRNA expression in Sertoli cells, but not in Leydig cells or spermatids. Overall, these data should aid further refinements to the interpretation and modeling of the in vivo disposition of OAT substrates. Specifically, expression in Sertoli cells suggests Oat6 may be an important determinant of blood-testis barrier function, with Oat6-mediated transport of estrone sulfate and DHEAS possibly representing a critical step in the maintenance of testicular steroidogenesis.
Rights
Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
Is Part Of
VCU Pharmaceutics Publications
Comments
Originally published at doi:10.1124/jpet.110.168765
PMCID: PMC2939676
Douglas H. Sweet was at the Medical University of South Carolina at the time of publication.