Received for publication March 4, 2008.
Revised July 19, 2008.
Accepted for publication July 22, 2008.

Enhancement of zidovudine uptake by dehydroepiandrosterone sulfate in rat syncytiotrophoblast cell line TR-TBT 18d-1

Abstract

Zidovudine (AZT), which is used for the prevention of mother-to-child transmission of HIV-1, is transplacentally transferred to the fetus across the blood-placenta barrier (BPB), which is composed of syncytiotrophoblasts. We recently showed that apical uptake of AZT by syncytiotrophoblasts is mediated by saturable transport system(s) in the TR-TBT 18d-1 cell line, and the cellular accumulation of AZT was increased in the presence of dehydroepiandrosterone sulfate (DHEAS). Here, we aimed to clarify the mechanism of this effect of DHEAS. Inhibitors of efflux transporters, including BCRP, P-gp and MRPs, had little effect on the cellular accumulation of AZT in TR-TBT 18d-1. Kinetic study revealed that rate constant for AZT uptake was greatly increased in the presence of 1 mM DHEAS. These results suggested that the effect of DHEAS was due to enhancement of the uptake process(es), rather than inhibition of efflux. When AZT uptake was analyzed according to the Michaelis-Menten equation, the estimated Michaelis constant K_m for AZT uptake in the presence of 1 mM DHEAS was lower than that in its absence, while maximum uptake velocity V_max and non-saturable uptake clearance k_ns were similar in the presence and absence of DHEAS, indicating that DHEAS may change the recognition characteristics of the transporter for AZT in TR-TBT 18d-1. Thus, the increase of AZT uptake in TR-TBT 18d-1 cells in the presence of DHEAS was concluded to be due to a DHEAS-induced change in the affinity of AZT uptake system, although the transporter responsible for AZT uptake has not been identified.

Key words: active transport, cellular transport, distribution, drug disposition, drug transport, drug-drug interactions, membrane transport, transporters