Abstract
OATP2B1 belongs to a highly conserved organic anion transporting polypeptide (OATP) family of transporters, involved in the cellular uptake of both endogenous and exogenous compounds. The reported substrates of human OATP2B1 include steroid conjugates, bile salts, and thyroid hormones, as well as pharmaceuticals. Human OATP2B1 has orthologous genes in other vertebrate species, including zebrafish (Danio rerio), a widely used model organism in biomedical and environmental research. Our previous studies showed that zebrafish Oatp2b1 was phylogenetically closest to mammalian OATP2B1/Oatp2b1 and that it shares a similar tissue expression pattern. In this study, we aimed at discovering whether zebrafish Oatp2b1 could be a functional ortholog of human and rodent OATP2B1. To test this hypothesis, our primary goal was to obtain the first in vitro and in silico insights related to the structure and potential substrate preferences of zebrafish Oatp2b1. We generated cells transiently and stably transfected with zebrafish Oatp2b1 cloned from zebrafish liver, constructed an Oatp2b1 homology model, developed transport activity assays with model fluorescent substrate Lucifer yellow, and finally utilized this assay to analyze the interaction of zebrafish Oatp2b1 with both physiological and xenobiotic substances. Apart from structure similarities, our data revealed the strongest interaction of zebrafish Oatp2b1 with bile acids, steroid sulfates, thyroid hormones, and bilirubin, as well as xenobiotics bromosulfophthalein and sulfasalazine, which indicates its functional orthology with human OATP2B1.
Highlights
Members of the organic anion transporting polypeptide superfamily (OATP in humans/Oatp in other animals) are transmembrane proteins involved in the trafficking of large amphipatic molecules across the plasma membrane of eukaryotes
We generated cells transiently and stably transfected with zebrafish Oatp2b1 cloned from zebrafish liver, constructed an Oatp2b1 homology model, developed transport activity assays with model fluorescent substrate Lucifer yellow, and utilized this assay to analyze the interaction of zebrafish Oatp2b1 with both physiological and xenobiotic substances
The data shown in this study represent the first insights related to the structure, substrate preferences and possible function of zebrafish Oatp2b1
Summary
Members of the organic anion transporting polypeptide superfamily (OATP in humans/Oatp in other animals) are transmembrane proteins involved in the trafficking of large amphipatic molecules across the plasma membrane of eukaryotes. OATPs/Oatps mediate the transport of a wide range of endogenous (steroid hormones, bile salts, prostaglandins) and exogenous compounds (pharmaceuticals, natural toxins) Their role in ADME processes (absorption, distribution, metabolism and elimination) has become increasingly recognized due to their involvement in the cellular uptake of drugs in tissues important for pharmacokinetics, such as the liver, kidney and intestines (Kindla et al, 2009). Unlike other members of this sub-family, OATP2B1/Oatp2b1 is ubiquitously expressed across tissues in humans and rats It is the third most expressed OATP in the basolateral hepatocyte membrane of the human liver (Kullak-Ublick et al, 2001; Tamai et al, 2000)
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