Interaction of Environmental Steroids with Organic Anion Transporting Polypeptide (Oatp1d1) in Zebrafish (Danio rerio)

摘要

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: 17-hydroxyprogesteroneclobetasol propionatespironolactone21-hydroxyprogesteronefludrocortisone 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. (c) 2018 SETAC