Abstract
The organic anion transporter OAT4 (SLC22A11) and organic anion transporting polypeptide OATP2B1 (SLCO2B1) are expressed in the basal membrane of the placental syncytiotrophoblast. These transporters mediate exchange whereby uptake of one organic anion is coupled to efflux of a counter-ion. In placenta, these exchangers mediate placental uptake of substrates for oestrogen synthesis as well as clearing waste products and xenobiotics from the fetal circulation. However, the identity of the counter-ion driving this transport in the placenta, and in other tissues, is unclear. While glutamate is not a known OAT4 or OATP2B1 substrate, we propose that its high intracellular concentration has the potential to drive accumulation of substrates from the fetal circulation. In the isolated perfused placenta, glutamate exchange was observed between the placenta and the fetal circulation. This exchange could not be explained by known glutamate exchangers. However, glutamate efflux was trans-stimulated by an OAT4 and OATP2B1 substrate (bromosulphothalein). Exchange of glutamate for bromosulphothalein was only observed when glutamate reuptake was inhibited (by addition of aspartate). To determine if OAT4 and/or OATP2B1 mediate glutamate exchange, uptake and efflux of glutamate were investigated in Xenopus laevis oocytes. Our data demonstrate that in Xenopus oocytes expressing either OAT4 or OATP2B1 efflux of intracellular [(14)C]glutamate could be stimulated by conditions including extracellular glutamate (OAT4), estrone-sulphate and bromosulphothalein (both OAT4 and OATP2B1) or pravastatin (OATP2B1). Cycling of glutamate across the placenta involving efflux via OAT4 and OATP2B1 and subsequent reuptake will drive placental uptake of organic anions from the fetal circulation.
Highlights
Many therapeutic drugs and environmental chemicals are potentially teratogenic in pregnancy
This study demonstrates for the first time that OAT4 and OATP2B1 mediate glutamate efflux and that, in the placenta, uptake of the OAT4 and OATP2B1 substrate BSP is coupled to release of glutamate
That glutamate can act as a counter-ion for these transporters is physiologically important, as its high intracellular concentration will provide a chemical gradient to drive placental uptake of OAT4 and OATP2B1 substrates from the fetal circulation
Summary
Many therapeutic drugs and environmental chemicals are potentially teratogenic in pregnancy. The OATs and OATPs are exchangers, mediating uptake of one molecule in exchange for efflux of another. In theory, this means that OAT4 and OATP2B1 could transport xenobiotics both to and from the fetal circulation. The exchanger xCT (SLC7A11) can transport glutamate and cystine in either direction but in practice will primarily mediate cystine uptake. This is because the high intracellular glutamate concentration will competitively inhibit cystine efflux via xCT while driving uptake of cystine by secondary active transport (Sato et al 1999)
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