Sulfation is a major pathway in humans for the biotransformation of estrogens. However, the nature of the enzymes that catalyze the sulfation of estrone (E1) and 17β-estradiol (E2) in human liver is unclear. Human liver contains at least three well-characterized cytoplasmic sulfotransferases, the thermostable (TS) and thermolabile (TL) forms of phenol sulfotransferase (PST) and dehydroepiandrosterone sulfotransferase (DHEA ST). Therefore, we determined optimal conditions for the assay of E1 and E2 ST activities in human hepatic cytosol to compare their properties and regulation with those of the three well-characterized human liver ST activities. Thermal inactivation studies showed that human liver E2 ST and TS PST had very similar thermal stabilities. The thermal inactivation profile of E1 ST suggested that this activity might be related to both DHEA ST and TS PST. Inhibition studies performed with 2,6-dichloro-4-nitrophenol (DCNP) also showed similar inhibition profiles for E2 ST and TS PST. Neither thermal inactivation nor DCNP inhibition studies indicated a possible relationship between TL PST activity and E1 or E2 sulfation. Experiments performed with 20 individual human liver samples showed highly significant correlations between activity levels of E2 ST and TS PST (r(s) = 0.944, p < 0.0001), E1 ST and DHEA ST (r(s) = 0.845, p < 0.0001), and, to a lesser degree, E1 ST and TS PST (r(s) = 0.608, p < 0.01). Ion exchange chromatography of a human liver preparation, followed by assay of all five ST activities, confirmed the important roles played by TS PST and DHEA ST in the sulfation of E2 and E1. Similar results were found by study of the elution patterns of ST activities after ion exchange chromatography of human jejunal mucosal preparations. Partially purified TL PST, however, was unable to catalyze the sulfate conjugation of either E1 or E2. All of these results were compatible with the conclusion that, in human liver, TS PST is the enzyme predominantly responsible for the sulfate conjugation of E2, DHEA ST is the major enzyme responsible for the sulfation of E1, and TL PST does not appear to catalyze the sulfation of either E1 or E2.
|Original language||English (US)|
|Number of pages||10|
|Journal||Drug Metabolism and Disposition|
|State||Published - 1992|
ASJC Scopus subject areas
- Pharmaceutical Science