Received for publication May 9, 2006.
Revised August 8, 2006.
Accepted for publication August 14, 2006.

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. While the expression of some members of this group like OATP-A or C is limited to special tissues like liver or brain, the organic anion transporting polypeptide 2B1 (OATP-B / 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 like 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 MDCKII cells. We could identify unconjugated androgens (e.g. testosterone) as potent inhibitors for OATP2B1. In contrast, gestagenes like progesterone enhance E3S uptake in a concentration dependent manner to up to 300 % of the control, accompanied by a significant decrease in OATP2B1 K_m value for E3S (control: K_m = 14 µM; in the presence of 31.6 µM progesterone K_m = 3.6 µM). Moreover, we could demonstrate that testosterone and progesterone are not substrates of OATP2B1, indicating an allosteric mechanism for the observed effects. Furthermore, we could show 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 like progesterone. These effects can have physiological consequences for the organ-specific uptake of steroids.

Key words: Sex hormones, Organic anion, Liver transporters