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

Tomohiro Nishimura, Yoshiaki Seki, Kazuko Sato, Takuya Chishu, Noriko Kose, Tetsuya Terasaki, Young Sook Kang, Yoshimichi Sai, Emi Nakashima

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

AZT (3′-azido-3′-deoxythymidine; zidovudine), which is used for the prevention of mother-to-child transmission of HIV-1, is trans-placentally 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.

Original languageEnglish
Pages (from-to)2080-2085
Number of pages6
JournalDrug Metabolism and Disposition
Volume36
Issue number10
DOIs
Publication statusPublished - 2008 Oct

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Dehydroepiandrosterone Sulfate
Zidovudine
Trophoblasts
Cell Line
P-Glycoproteins
P-Glycoprotein
Placenta
HIV-1
Fetus
Mothers
Breast Neoplasms

ASJC Scopus subject areas

  • Pharmacology
  • Pharmaceutical Science

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enhancement of zidovudine uptake by dehydroepiandrosterone sulfate in rat syncytiotrophoblast cell line TR-TBT 18d-1. / Nishimura, Tomohiro; Seki, Yoshiaki; Sato, Kazuko; Chishu, Takuya; Kose, Noriko; Terasaki, Tetsuya; Kang, Young Sook; Sai, Yoshimichi; Nakashima, Emi.

In: Drug Metabolism and Disposition, Vol. 36, No. 10, 10.2008, p. 2080-2085.

Research output: Contribution to journalArticle

Nishimura, Tomohiro ; Seki, Yoshiaki ; Sato, Kazuko ; Chishu, Takuya ; Kose, Noriko ; Terasaki, Tetsuya ; Kang, Young Sook ; Sai, Yoshimichi ; Nakashima, Emi. / enhancement of zidovudine uptake by dehydroepiandrosterone sulfate in rat syncytiotrophoblast cell line TR-TBT 18d-1. In: Drug Metabolism and Disposition. 2008 ; Vol. 36, No. 10. pp. 2080-2085.
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abstract = "AZT (3′-azido-3′-deoxythymidine; zidovudine), which is used for the prevention of mother-to-child transmission of HIV-1, is trans-placentally 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.",
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AU - Chishu, Takuya

AU - Kose, Noriko

AU - Terasaki, Tetsuya

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