title: Modification of OATP2B1-mediated transport by steroid hormones.
abstract: The family of the organic anion transporting polypeptides forms an increasing group of uptake transport proteins with a wide substrate spectrum. Although the expression of some members of this group, such as organic anion transporting polypeptide (OATP)-A or C, is limited to special tissues (such as liver or brain), the organic anion transporting polypeptide 2B1 (OATPB/SLCO2B1) is expressed in many organs, including liver, placenta, mammary gland, brain, and intestine. However, little is known about its function in those tissues because only a limited number of compounds, such as dehydroepiandrosterone-sulfate (DHEAS) and estrone-3-sulfate (E3S), have been characterized as OATP2B1 substrates. To further elucidate the role of OATP2B1 on steroid transport, we examined the influence of steroid hormones on OATP2B1-mediated E3S and DHEAS uptake using OATP2B1-overexpressing Madin-Darby canine kidney II cells. We identified unconjugated androgens (e.g., testosterone) as potent inhibitors for OATP2B1. In contrast, gestagenes such as progesterone enhanced E3S uptake in a concentration-dependent manner to up to 300% of the control, accompanied by a significant decrease in the OATP2B1 K(m) value for E3S (control, K(m) = 14 microM; in the presence of 31.6 muM progesterone, K(m) = 3.6 microM). Moreover, we demonstrated that testosterone and progesterone are not substrates of OATP2B1, indicating an allosteric mechanism for the observed effects. Furthermore, we showed that progesterone enhances the OATP2B1-dependent pregnenolone sulfate transport. Taken together, the results indicate functional modification of OATP2B1-mediated E3S and DHEAS as well as pregnenolone sulfate transport through steroid hormones such as progesterone. These effects can have physiological consequences for the organ-specific uptake of steroids.
authors.affiliation: Department of Pharmacology, Research Center of Pharmacology and Experimental Therapeutics, Friedrich-Loeffler-Str. 23d, 17487 Greifswald, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Grube
authors.forename: Kathleen
authors.initials: K
authors.lastname: Köck
authors.forename: Susanne
authors.initials: S
authors.lastname: Karner
authors.forename: Sebastian
authors.initials: S
authors.lastname: Reuther
authors.forename: Christoph A
authors.initials: CA
authors.lastname: Ritter
authors.forename: Gabriele
authors.initials: G
authors.lastname: Jedlitschky
authors.forename: Heyo K
authors.initials: HK
authors.lastname: Kroemer
mesh_terms: D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D019314:Dehydroepiandrosterone Sulfate / Q000493:pharmacokinetics; D004285:Dogs; D004970:Estrone / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D015870:Gene Expression; D006801:Humans; D007553:Isotope Labeling; D007700:Kinetics; D015735:Mifepristone / Q000494:pharmacology; D027361:Organic Anion Transporters / Q000378:metabolism*; D011284:Pregnenolone / Q000494:pharmacology; D011374:Progesterone / Q000494:pharmacology; D013256:Steroids / Q000494:pharmacology*; D013739:Testosterone / Q000494:pharmacology
chemical_list: D027361:Organic Anion Transporters; C450859:SLCO2B1 protein, human; D013256:Steroids; C018370:pregnenolone sulfate; D004970:Estrone; D015735:Mifepristone; D013739:Testosterone; D011374:Progesterone; D019314:Dehydroepiandrosterone Sulfate; D011284:Pregnenolone; C017296:estrone sulfate