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Human organic anion transporter 4 (hOAT4) belongs to a family of organic anion transporters that play critical roles in the body disposition of clinically important drugs, including anti-human immunodeficiency virus therapeutics, anti-tumor drugs, antibiotics, antihypertensives, and anti-inflammatories, hOAT4 is abundantly expressed in the placenta. In the current study, we examined the regulation of hOAT4 by pregnancy-specific hormones progesterone (P4) and 17[beta]-estradiol ([E.sub.2]) and by protein kinase C (PKC) in human placental BeWo cells. P4 induced a time- and concentration-dependent down-regulation of hOAT4 transport activity, whereas [E.sub.2] had no effect on hOAT4 function. The downregulation of hOAT4 activity by P4 mainly resulted from a decreased cell surface expression without a change in total cell expression of the transporter, kinetically revealed as a decreased [V.sub.max] without significant change in Kin. Activation of PKC by phorbol 12,13-dibutyrate also resulted in an inhibition of hOAT4 activity through a decreased cell surface expression of the transporter. However, P4-induced downregulation of hOAT4 activity could not be prevented by treating hOAT4-expressing cells with the PKC inhibitor staurosporine. We concluded that both P4 and activation of PKC inhibited hOAT4 activity through redistribution of the transporter from cell surface to the intracellular compartments. However, [P.sub.4] regulates hOAT4 activity by mechanisms independent of PKC pathway. acute regulation doi:10.1152/ajpendo.00696.2006

Zhou, Fanfan, Kunihiko Tanaka, Michael J. Soares, and Guofeng You. Characterization of an organic anion transport system in a placental cell line. Am J Physiol Endocrinol Metab 285: E1103-E1109, 2003. First published August 5, 2003; 10.1152/ajpendo.00182.2003.--Transporters within the placenta play a crucial role in the distribution of nutrients and xenobiotics across the maternal-fetal interface. An organic anion transport system was identified on the apical membrane of the rat placenta cell line HRP-1, a model for the placenta barrier. The apical uptake of [sup.3.H]-labeled organic anion estrone sulfate in HRP-1 cells was saturable ([K.sub.m] = 4.67 [micro]M), temperature and [Na.sup.+] dependent, [Li.sup.+] tolerant, and pH sensitive. The substrate specificity of the transport system includes various steroid sulfates, such as [beta]-estradiol 3,17-disulfate, 17[beta]-estradiol 3-sulfate, and dehydroepiandrosterone 3-sulfate (DHEAS) but does not include taurocholate, p-aminohippuric acid (PAH), and tetraethyl-ammonium. Preincubation of HRP-1 cells with 8-bromo-cAMP (a cAMP analog) and forskolin (an adenylyl cyclase activator) acutely stimulated the apical transport activity. This stimulation was further enhanced in the presence of IBMX (a phosphodiesterase inhibitor). Together these data show that the apical membrane of HRP-1 cells expresses an organic anion transport system that is regulated by cellular cAMP levels. This transport system appears to be different from the known taurocholate-transporting organic anion-transporting polypeptides and PAH-transporting organic anion transporters, both of which also mediate the transport of estrone sulfate and DHEAS. placenta; organic anion; transporters