Sulfation of budesonide by human cytosolic sulfotransferase, dehydroepiandrosterone-sulfotransferase (DHEA-ST).

Budesonide, a synthetic glucocorticosteroid, is used in the treatment of asthma and allergic reactions, rhinitis, and inflammatory bowel disease. It is distributed as a mixture of two epimers, 22R and 22S, and has a high ratio of topical to systemic activity due to extensive first-pass metabolism to metabolites with minimal activity. Previous studies have shown that the epimers are metabolized by the cytochrome P450 monooxygenase system. Metabolism and inactivation of the epimers by the phase II enzymes has not been well characterized. This study describes the conjugation of budesonide by human cytosolic sulfotransferases (SULTs). Seven human SULTs were analyzed to determine which were capable of catalyzing the sulfation of the epimers of budesonide. Only dehydroepiandrosterone-sulfotransferase (DHEA-ST, SULT2A1) was capable of forming a sulfated budesonide product. The epimeric forms of budesonide display different kinetic activities with the 22R epimer having a 3.5-fold greater rate of sulfation activity than the 22S epimer. The structure of budesonide shows two hydroxyl sites that are potential sites for sulfate conjugation, but analysis by mass spectrometry indicates the formation of only a monosulfated budesonide product. A modeling approach was used to define the site of sulfation as that of the 21-hydroxyl group. Although sulfation of budesonide by DHEA-ST may not be an important factor in its use as an antiasthmatic, intestinal and hepatic sulfation will be important for its proposed systemic use as an anti-inflammatory agent.