RT Journal Article
SR Electronic
T1 Enhancement of Zidovudine Uptake by Dehydroepiandrosterone Sulfate in Rat Syncytiotrophoblast Cell Line TR-TBT 18d-1
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 2080
OP 2085
DO 10.1124/dmd.108.021345
VO 36
IS 10
A1 Tomohiro Nishimura
A1 Yoshiaki Seki
A1 Kazuko Sato
A1 Takuya Chishu
A1 Noriko Kose
A1 Tetsuya Terasaki
A1 Young-Sook Kang
A1 Yoshimichi Sai
A1 Emi Nakashima
YR 2008
UL http://dmd.aspetjournals.org/content/36/10/2080.abstract
AB AZT (3′-azido-3′-deoxythymidine; zidovudine), 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, 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 breast cancer resistance protein, P-glycoprotein, and multidrug resistance proteins, had little effect on the cellular accumulation of AZT in TR-TBT 18d-1. Kinetic study revealed that the rate constant for AZT uptake was greatly increased in the presence of 1 mM DHEAS. These results suggested that the effect of DHEAS was because of 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, Km, for AZT uptake in the presence of 1 mM DHEAS was lower than that in its absence, whereas maximum uptake velocity, Vmax, and nonsaturable uptake clearance, kns, 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 because of a DHEAS-induced change in the affinity of AZT uptake system, although the transporter responsible for AZT uptake has not been identified. The American Society for Pharmacology and Experimental Therapeutics