Sulfation of raloxifene and 4-hydroxytamoxifen by human cytosolic sulfotransferases
Sulfation of raloxifene and 4-hydroxytamoxifen by human cytosolic sulfotransferases
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DOI：
10.1124/dmd.105.006551
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发表时间：
2006-03-01
影响因子：
3.9
通讯作者：
Falany, CN
中科院分区：
文献类型：
--
作者：
Falany, JL;Pilloff, DE;Falany, CN
雷洛昔芬和4-羟他莫昔芬（4-OHT）是治疗骨质疏松症和乳腺癌的重要雌激素相关药物。硫酸化参与了人体组织中这两种化合物的代谢和失活，尽管参与它们结合的硫转移酶（SULT）异构体尚未得到很好的描述。研究了7种表达的SULT异构体对雷洛昔芬和4-OHT的硫酸能力。雷洛昔芬被所有7种SULT同工异构体偶联，而4-OHT仅被SULTs 1A1、1E1和2A1偶联。雷洛昔芬和4-OHT磺化的表征表明，磺化可以在治疗浓度下发生。SULT1E1对4-OHT磺化的K-m最小（0.2 μ M）， sult1a1对雷洛昔芬磺化的K-m最小（0.3 μ M）。SULT1E1是唯一表现出可检测水平的雷洛昔芬增殖活性的异构体。雷洛昔芬在SULT1E1活性位点的相互作用模型表明，雷洛昔芬的两个羟基都可以很容易地定位在3'-磷酸腺苷5'-磷酸硫酸酯的磺酰基和催化重要的His107残基附近。雷洛昔芬和4-OHT磺化活性在所有被测的人肝细胞溶胶中均可检测到。在同一月经周期的增殖期和分泌期获得的正常妇女子宫内膜活检制备的细胞质中检测到4-OHT硫酸化。相反，雷洛昔芬硫酸化仅在分泌期细胞质中检测到，与SULT1E1活性相关。总之，几种人类SULT异构体能够硫酸化雷洛昔芬和4-OHT。单个SULT亚型的组织特异性表达可能在这些化合物活性的调节中起重要作用。
Raloxifene and 4-hydroxytamoxifen (4-OHT) are important estrogenrelated drugs used in the treatment of osteoporosis and breast cancer. Sulfation is involved in the metabolism and inactivation of both compounds in human tissues, although the sulfotransferase (SULT) isoforms involved in their conjugation have not been well described. The ability of seven expressed SULT isoforms to sulfate raloxifene and 4-OHT was investigated. Raloxifene was conjugated by all seven SULT isoforms tested, whereas 4-OHT was conjugated only by SULTs 1A1, 1E1, and 2A1. Characterization of raloxifene and 4-OHT sulfation demonstrates that sulfation can occur at therapeutic concentrations. SULT1E1 displayed the lowest K-m (0.2 mu M) for 4-OHT sulfation and SULT2A1 the lowest (0.3 mu M) for raloxifene sulfation. SULT1E1 was the only isoform exhibiting detectable levels of raloxifene disulfation activity. Modeling of the interactions of raloxifene in the active site of SULT1E1 indicates that both hydroxyl groups of raloxifene can be readily positioned in proximity to the sulfonyl group of 3'-phosphoadenosine 5'-phosphosulfate and the catalytically important His107 residue. Both raloxifene and 4-OHT sulfation activities were detectable in all human liver cytosols tested. 4-OHT sulfation was detected in cytosol prepared from endometrial biopsies of normal women obtained during the proliferative and secretory phases of the same menstrual cycle. In contrast, raloxifene sulfation was detectable only in secretory phase cytosols in association with SULT1E1 activity. In summary, several human SULT isoforms are capable of sulfating raloxifene and 4-OHT. Tissue-specific expression of the individual SULT isoforms may have important roles in the regulation of the activity of these compounds.