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METABOLISM, TRANSPORT, AND PHARMACOGENOMICS

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

Department of Pharmaceutical Sciences (H.S., L.L., K.S.P.), Leslie Dan Faculty of Pharmacy, and Department of Pharmacology (K.S.P.), Faculty of Medicine, University of Toronto, Toronto, Canada

Changes in the disposition of estradiol 17-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 with CC531 cells intraportally to induce metastatic tumors (n = 5) or with phosphate-buffered saline 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 the reservoir perfusate, and the total (9.19 ± 1.33 versus 8.18 ± 0.94 ml/min) and biliary (4.94 ± 1.07 versus 4.60 ± 0.86 ml/min) clearances were similar in both groups (P > 0.05). The metabolic clearance of E₂17G was higher in the tumor group (4.60 ± 0.64 versus 3.23 ± 0.23 ml/min, P < 0.05). 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 < 0.05). All of the observations were captured by modeling. From modeling, we showed that reduction of the high influx clearance (546 to 283 ml/min) failed to lower the total clearance of E₂17G, whereas up-regulation of Sult1e1 increased the E₂17G sulfation clearance (2.56 to 3.69 ml/min) in livers with metastatic tumors.

Address correspondence to: Dr. K. Sandy Pang, Leslie Dan Faculty of Pharmacy, University of Toronto, 144 College St., Toronto, ON M5S 3M2, Canada. E-mail: ks.pang{at}utoronto.ca