Progesterone Inhibits Folic Acid Transport in Human Trophoblasts |
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Authors: | Elisa Keating Pedro Gonçalves Clara Lemos Fernanda Costa Isabel Campos Sylvia B Smith Christy C Bridges Fátima Martel |
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Institution: | Department of Biochemistry (U38-FCT), Faculty of Medicine of Porto, University of Porto, Porto 4200-319, Portugal. |
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Abstract: | 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. (3)H]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, (3)H]FA uptake and efflux were inhibited by progesterone (200 microM). An inhibitory effect of progesterone upon (3)H]FA uptake and efflux was also observed in human cytotrophoblasts. Moreover, verapamil and ss-estradiol also reduced (3)H]FA efflux in these cells. Inhibition of (3)H]FA uptake in BeWo cells by progesterone seemed to be very specific since other tested steroids (beta-estradiol, corticosterone, testosterone, aldosterone, estrone and pregnanediol) were devoid of effect. However, efflux was also inhibited by beta-estradiol and corticosterone and stimulated by estrone. Moreover, the effect of progesterone upon the uptake of (3)H]FA by BeWo cells was concentration-dependent (IC(50 )= 65 range 9-448] microM) and seems to involve competitive inhibition. Also, progesterone (1-400 microM) did not affect either (3)H]FA uptake or efflux at an external acidic pH. Finally, inhibition of (3)H]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. |
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Keywords: | Folic acid homeostasis Placenta Progesterone Steroid ABC transporter Reduced folate carrier |
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