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Regulation of human organic anion transporter 4 by progesterone and protein kinase C in human placental BeWo cells

¹Department of Pharmaceutics, Rutgers, The State University of New Jersey, and ²Department of Pharmacology, University of Medicine and Dentistry-Robert Wood Johnson Medical School, Piscataway, New Jersey

Submitted 19 December 2006 ; accepted in final form 5 March 2007

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-estradiol (E₂) and by protein kinase C (PKC) in human placental BeWo cells. P₄ induced a time- and concentration-dependent downregulation of hOAT4 transport activity, whereas E₂ 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_max without significant change in K_m. 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, P₄ regulates hOAT4 activity by mechanisms independent of PKC pathway.

acute regulation

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