Interactions of the human cytosolic sulfotransferases and steroid sulfatase in the metabolism of tibolone and raloxifene

Abstract

Sulfation is important in the metabolism and inactivation of steroidal compounds and hormone replacement therapeutic (HRT) agents in human tissues. Although generally inactive, many steroid sulfates are hydrolyzed to their active forms by sulfatase activity. Therefore, the specific sulfotransferase (SULT) isoforms and the levels of steroid sulfatase (STS) activity in tissues are important in regulating the activity of steroidal and HRT compounds. Tibolone (Tib) is metabolized to three active metabolites and all four compounds are readily sulfated. Tib and the Δ4-isomer are sulfated at the 17β-OH group by SULT2A1 and the 17-sulfates are resistant to hydrolysis by human placental STS. 3α-OH and 3β-OH Tib can form both 3-and 17-monosulfates as well as disulfates. Only the 3β-sulfates are susceptible to STS hydrolysis. Raloxifene monosulfation was catalyzed by at least seven SULT isoforms and SULT1E1 also synthesizes raloxifene disulfate. SULT1E1 forms both monosulfates in a ratio of approximately 8:1 with the more abundant monosulfate migrating on HPLC identical to the SULT2A1 synthesized monosulfate. The raloxifene monosulfate formed by both SULT isoforms is sensitive to STS hydrolysis whereas the low abundance monosulfate formed by SULT1E1 is resistant. The benzothiophene sulfates of raloxifene and arzoxifene were hydrolyzed by STS whereas the raloxifene 4′-phenolic sulfate was resistant. These results indicate that tissue specific expression of SULT isoforms and STS could be important in the inactivation and regeneration of the active forms of HRT agents.

24-Hydroxycholesterol Sulfation by Human Cytosolic Sulfotransferases: Formation of Monosulfates and Disulfates, Molecular Modeling, Sulfatase Sensitivity, and Inhibition of Liver X Receptor Activation

“…Treatment of the initial reaction products with STS resulted in the total loss of only the 9.0 min or 3-monosulfate peak. This result is consistent with the selectivity of STS for the hydrolysis of 3␤-sulfates compared with 3␣-sulfates on steroidal compounds (Falany and Falany, 2007). Figure 5B shows the elution of the 24-OHChol-3, 24-disulfate formed by SULT2A1.…”

“…The monosulfates also showed different elution times. The 3-sulfate was assigned by its sensitivity to STS hydrolysis that is specific for the 3-position of sterols (HernandezGuzman et al, 2001;Iwamori, 2005;Falany and Falany, 2007), differential formation by SULT2A1 and SULT2B1b, and MS/MS analysis. SULT2B1b is highly selective for the 3-position of sterols and docking affinities of 24-OHChol in the active sites of SULT2A1 and SULT2B1b.…”

“…This generated an active but relatively unstable preparation of native SULT2B1b (Meloche and Falany, 2001;Falany et al, 2006). STS was purified from human full-term placenta using the method of Hernandez-Guzman et al (2001) as described previously (Falany and Falany, 2007). In brief, fresh term human placental tissue was obtained from the Tissue Procurement Service of the University of Alabama at Birmingham Comprehensive Cancer Center.…”

“…However, the sulfates of some hormonally active drugs are resistant to STS. The 3␣-sulfate of tibolone is resistant to STS, whereas the 3␤-sulfate of tibolone is hydrolyzed (Falany and Falany, 2007). In addition, the benzothiophene sulfate of raloxifene is hydrolyzed by STS, whereas the phenolic sulfate of raloxifene is resistant (Falany and Falany, 2007).…”

Quantitative Evaluation of the Expression and Activity of Five Major Sulfotransferases (SULTs) in Human Tissues: The SULT “Pie”

“…SULT1A3, found only in primates, sulfates catecholamines with high selectivity (Dajani et al, 1998;Eisenhofer et al, 1999), and SULT1B1 displays a similar substrate profile to SULT1A1 but with much higher K m values toward most substrates (Tabrett and Coughtrie, 2003;Riches et al, 2007). SULT1E1 and SULT2A1 are both steroid SULTs (selective for estrogens and androgens, respectively), which also sulfate drugs and other xenobiotics (e.g., Forbes-Bamforth and Coughtrie, 1994;Shibutani et al, 1998;Falany and Falany, 2007). The sterol/steroid SULT2B1a and SULT2B1b proteins are not significantly expressed in gastrointestinal or hepatic tissues (Meloche and Falany, 2001;Teubner et al, 2007) (although there is some expression in lung) (He et al, 2005), and SULT1C enzymes are expressed primarily in the fetus (Stanley et al, 2005), with some SULT1C1 in the adult stomach (Teubner et al, 2007).…”