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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on August 8, 2006; DOI: 10.1124/jpet.106.108860

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Received for publication June 5, 2006.
Revised August 6, 2006.
Accepted for publication August 7, 2006.

Increased Estrogen Sulfation of Estradiol 17{beta}-D Glucuronide in Metastatic Tumor Rat Livers

Huadong Sun 1, Lichuan Liu 1, K. Sandy Pang 2*

1 Leslie Dan Faculty of Pharmacy, University of Toronto 2 Leslie Dan Faculty of Pharmacy, and Department of Pharmacology, University of Toronto

* Address correspondence to: E-mail: ks.pang{at}utoronto.ca

Abstract

Changes in disposition of estradiol 17{beta}-D glucuronide (E217G), a substrate of the organic-anion transporting polypeptide family (Oatp) and multidrug resistance-associated protein 2 (Mrp2), were examined in livers of Male Wag/Rij rats that were injected CC531 cells intraportally to induce metastatic tumors (n=5), or PBS for sham-operated controls (n=4). Multiple indicator dilution, single pass liver perfusions revealed extremely high influx clearances of [3H]E217G (> 190 ml/min) in both groups. In recirculating liver perfusions, [3H]E217G decayed monoexponentially in reservoir perfusate, and the total (9.19 ± 1.33 vs. 8.18 ± 0.94 ml/min) and biliary (4.94 ± 1.07 vs. 4.60 ± 0.86 ml/min) clearances were similar in both groups (P >.05). The metabolic clearance of E217G was higher in the tumor group (4.60 ± 0.64 vs. 3.23 ± 0.23 ml/min, P <.05). E23S17G, the 3-sulfate metabolite, whose identity was confirmed by mass spectrometry, appeared only in bile and not perfusate. Liver microsomal incubations of E2335S17G and [3H] estrone sulfate revealed similar sulfatase activities between the tumor and sham livers, albeit the activities were much lower for E2335S17G. Oatp1a1 and Oatp1b2 protein expression in liver membrane fragments was reduced by 42% and 38%, respectively, whereas that of cytosolic estrogen sulfotransferase (Sult1e1) was significantly increased (41%) with tumor (P <.05). All of the observations were captured by modeling. Reduction of the high influx clearance (546 to 283 ml/min) failed to lower the total clearance of E217G. However, upregulation of Sult1e1 increased the E217G sulfation clearance (2.56 to 3.69 ml/min) in livers with metastatic tumors.


Key words: drug resistance, estradiol 17{beta} glucuronide, estrogen sultotransferases, futile cycling, liver metastatic tumors, transporters


This article has been cited by other articles:


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 Am. J. Physiol. Gastrointest. Liver Physiol.Home page
L. Liu, H. Sun, W. Y. Valji, and K. S. Pang
Transporters, enzymes, and enalapril removal in a rat (CC531-induced) liver metastatic model
Am J Physiol Gastrointest Liver Physiol, November 1, 2007; 293(5): G1078 - G1088.
[Abstract] [Full Text] [PDF]


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