Received for publication July 26, 2005.
Revised December 9, 2005.
Accepted for publication December 12, 2005.

Sulfation of Raloxifene and 4-Hydroxytamoxifen by Human Cytosolic Sulfotransferases

Abstract

Raloxifene and 4-hydroxytamoxifene (4-OHT) are important estrogen-related 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 Km (0.2 µM) for 4-OHT sulfation and SULT2A1 the lowest (0.3 µM) 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 PAPS 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.

Key words: anticancer agents, drug disposition, endocrine regulation, extrahepatic drug metabolism, hormonal regulation, mass spectrometry, phase II drug metabolism, steroids, sulfate conjugation, sulfotransferases

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