Abstract
The sex steroid hormone estrogen down-regulates renal organic cation (OC) transport in animals, and it may contribute to sex-related differences in xenobiotic accumulation and excretion. Also, the presence of various endocrine-disrupting chemicals, i.e., environmental chemicals that possess estrogenic activity (e.g., xenoestrogens) may down-regulate various transporters involved in renal accumulation and excretion of xenobiotics. The present study characterizes the mechanism by which long-term (6-day) incubation with physiological concentrations of 17β-estradiol (E2) or the xenoestrogens diethylstilbestrol (DES) and bisphenol A (BPA) regulates the basolateral membrane transport of the OC tetraethylammonium (TEA) in opossum kidney (OK) cell renal cultures. Both 17β-E2 and the xenoestrogen DES produced a dose- and time-dependent inhibition of basolateral TEA uptake in OK cell cultures, whereas the weakly estrogenic BPA had no effect on TEA uptake. Treatment for 6 days with either 1 nM 17β-E2 or DES reduced TEA uptake by ∼30 and 40%, respectively. These effects were blocked completely by the estrogen receptor antagonist ICI 182780 (Faslodex, fulvestrant), suggesting that these estrogens regulate OC transport through the estrogen receptor, which was detected (estrogen receptor α) in OK cell cultures by reverse transcription-polymerase chain reaction. The Jmax value for TEA uptake in 17β-E2- and DES-treated OK cell cultures was ∼40 to 50% lower than for ethanol-treated cultures, whereas Kt was unaffected. This reduction in transport capacity was correlated with a reduction in OC transporter OCT1 protein expression following treatment with both agents.
Footnotes
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This work was supported in part by Grants DK062097, DK58251, and ES06694 from the National Institutes of Health. R.M.P. was supported by Ruth L. Kirschstein National Research Service Award Training Grant HL07249 and individual fellowship (Grant DK075242) from the National Institutes of Health.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.107.126748.
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ABBREVIATIONS: OC, organic cation; OCT, organic cation transporter; TEA, tetraethylammonium; BPA, bisphenol A; DES, diethylstilbestrol, 17β-E2, 17-β estradiol; OK, opossum kidney; BSA, bovine serum albumin; WB, Waymouth's buffer; PBS, phosphate-buffered saline; PBS-T, phosphate-buffered saline-Tween 20; ER, estrogen receptor; RT, reverse transcription; PCR, polymerase chain reaction; bp, base pair(s); EtOH, ethanol.
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↵ The online version of this article (available at http://jpet.aspetjournals.org) contains supplemental material.
- Received June 4, 2007.
- Accepted August 6, 2007.
- The American Society for Pharmacology and Experimental Therapeutics
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