环境中类固醇激素与斑马鱼(Danio rerio)体内有机阴离子转运多肽(Oatp1d1)的相互作用

环境中类固醇激素具有很高的生物活性，在水环境中又普遍存在，因而对鱼类健康造成威胁。目前，对鱼体内类固醇激素的吸收过程和毒代动力学知之甚少，特别是其中细胞膜转运体的作用。我们考察了17种内源性和环境中类固醇激素与斑马鱼体内有机阴离子摄取性转运体Oatp1d1的相互作用，Oatp1d1在斑马鱼的肝脏和肾脏中有显著表达。我们选择了不同类别的类固醇激素，包括雄烯二酮(A4)、黄体酮(P4)及其代谢物、糖皮质激素和螺旋内酯甾酮(竞争性抑制萤光黄(Lucifer Yellow, LY)的吸收)。半数抑制效应浓度(IC₅₀)通过S形抑制曲线获得，P4的IC₅₀最小，其他IC₅₀由大到小排列为:17α-羟基黄体酮>丙酸氯倍他索>螺旋内酯甾酮>21-羟基黄体酮>醋酸氟氢可的松和其他的糖皮质激素。类固醇激素的亲脂性与Oatp1d1相互作用的活性呈正相关关系。我们的数据表明不同类别的类固醇激素与Oatp1d1的相互作用活性不同，或为吸收，或为抑制，或吸收和抑制。如此可知类固醇激素会介入内源性底物的转运过程，以致相关的生理过程。同时，类固醇激素可通过竞争性抑制作用改变环境污染物的细胞贩运。 精选自Raffael Alois Willi, Karl Fent. Interaction of environmental steroids with organic anion transporting polypeptide (Oatp1d1) in zebrafish (Danio rerio). Environmental Toxicology and Chemistry,2018,37:2670-2676.
详情请见 https://doi.org/10.1002/etc.4231

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

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, particularly the role of cell membrane transporters. Here we investigated the interaction of 17 endogenous and environmental steroids with zebrafish organic anion uptake transporter Oatp1d1 that is prominently expressed liver and kidneys. We selected steroids of different classes including androstenedione (A4), progesterone (P4) and metabolites, as well as glucocorticoids and spironolactone by competitive inhibition of Lucifer Yellow (LY) uptake. The half-maximal inhibition (IC₅₀) values derived from sigmoid inhibition curves were lowest for P4 followed by the following order of increasing IC₅₀ values: 17?-hydroxyprogesterone > clobetasol propionate > spironolactone > 21?-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 and/or as inhibitors. 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.