Interaction of environmental steroids with organic anion transporting polypeptide (Oatp1d1) in zebrafish (Danio rerio)

Abstract

Steroid hormones in the aquatic environment may pose a risk to fish health due to their ubiquitous presence and high biological activity. At present, the uptake process and toxicokinetics of steroids in fish are poorly known, in particular the role of cell membrane transporters. We investigated the interaction of 17 endogenous and environmental steroids with the zebrafish organic anion transporting peptide (Oatp1d1) uptake transporter, which is prominently expressed in liver and kidneys. We selected steroids of different classes including androstenedione (A4), progesterone (P4), and its metabolites, as well as glucocorticoids and spironolactone, and analyzed their interaction with Oatp1d1 by competitive inhibition of the uptake of the fluorescent substrate Lucifer Yellow. The half-maximal inhibition (IC50) values derived from sigmoid inhibition curves were lowest for P4, and the order of increasing IC50 values was as follows: 17α-hydroxyprogesterone > clobetasol propionate > spironolactone > 21α-hydroxyprogesterone > fludrocortisone acetate and additional glucocorticoids. The interaction activity showed a positive correlation with the lipophilicity of the steroids. Our data show that different classes of steroids interact with Oatp1d1 with different activity (either by uptake or inhibition, or both). This is of importance, because in consequence, steroids may interfere with the transport of endogenous substrates, and thus physiological processes. Moreover, steroids may alter cellular trafficking of environmental contaminants by competitive inhibition of this transporter. Environ Toxicol Chem 2018;37:2670-2676. © 2018 SETAC.

A Review of P-Glycoprotein Function and Regulation in Fish

“…Membrane-permeable molecules require import proteins for the same reasons that they require export proteins including P-gp: active transport moves these molecules across barriers much faster than passive diffusion, and allows the organism to maintain substrate concentrations that are substantially different from passive equilibrium concentrations [4,9,99]. These import proteins share a very similar set of substrates and inhibitors with P-gp [1,[100][101][102]. This common substrate base is expected for an integrated system that controls the movement of compounds across barriers: each substrate molecule needs to be sequentially imported then exported in order to cross an epithelial cell, thus the importers and exporters in the same cell will transport a shared set of substrates.…”