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

Abstract

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 (P(4)) and 17beta-estradiol (E(2)) and by protein kinase C (PKC) in human placental BeWo cells. P(4) induced a time- and concentration-dependent downregulation of hOAT4 transport activity, whereas E(2) had no effect on hOAT4 function. The downregulation of hOAT4 activity by P(4) 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, P(4)-induced downregulation of hOAT4 activity could not be prevented by treating hOAT4-expressing cells with the PKC inhibitor staurosporine. We concluded that both P(4) and activation of PKC inhibited hOAT4 activity through redistribution of the transporter from cell surface to the intracellular compartments. However, P(4) regulates hOAT4 activity by mechanisms independent of PKC pathway.