The aim of this work was to test the putative involvement of members of the ABC superfamily of transporters on folic acid (FA) cellular homeostasis in the human placenta. [3H]FA uptake and efflux in BeWo cells were unaffected or hardly affected by multidrug resistance 1 (MDR1) inhibition (with verapamil), multidrug resistance protein (MRP) inhibition (with probenecid) or breast cancer resistance protein (BCRP) inhibition (with fumitremorgin C). However, [3H]FA uptake and efflux were inhibited by progesterone (200 μM). An inhibitory effect of progesterone upon [3H]FA uptake and efflux was also observed in human cytotrophoblasts. Moreover, verapamil and ß-estradiol also reduced [3H]FA efflux in these cells. Inhibition of [3H]FA uptake in BeWo cells by progesterone seemed to be very specific since other tested steroids (β-estradiol, corticosterone, testosterone, aldosterone, estrone and pregnanediol) were devoid of effect. However, efflux was also inhibited by β-estradiol and corticosterone and stimulated by estrone. Moreover, the effect of progesterone upon the uptake of [3H]FA by BeWo cells was concentration-dependent (IC50 = 65 [range 9–448] μM) and seems to involve competitive inhibition. Also, progesterone (1–400 μM) did not affect either [3H]FA uptake or efflux at an external acidic pH. Finally, inhibition of [3H]FA uptake by progesterone was unaffected by either 4-acetamido-4′-isothiocyanato-2,2′-stilbenedisulfonic acid (SITS), a known inhibitor of the reduced folate carrier (RFC), or an anti-RFC antibody. These results suggest that progesterone inhibits RFC. In conclusion, our results show that progesterone, a sterol produced by the placenta, inhibits both FA uptake and efflux in BeWo cells and primary cultured human trophoblasts.
The Journal of Membrane Biology – Springer Journals
Published: Aug 9, 2007
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