Sulfation of 6-hydroxymelatonin, N-acetylserotonin and 4-hydroxyramelteon by the human cytosolic sulfotransferases (SULTs)

Abstract

1. This study aimed to investigate the involvement of sulfation in the metabolism of 6-hydroxymelatonin (6-OH-Mel), N-acetylserotonin (NAS) and 4-hydroxyramelteon (4-OH-Ram), and to identify and characterize the human cytosolic sulfotransferases (SULTs) capable of sulfating these drug compounds.

2. A systematic analysis using 13 known human SULTs revealed that SULT1A1 displayed the strongest activity in catalyzing the sulfation of 6-OH-Mel and 4-OH-Ram, whereas SULT1C4 exhibited the strongest sulfating-activity towards NAS. pH-dependence and kinetic parameters of these SULT enzymes in mediating the sulfation of respective drug compounds were determined. A metabolic labeling study showed the generation and release of [³⁵S]sulfated 6-OH-Mel, NAS and 4-OH-Ram by HepG2 human hepatoma cells and Caco-2 human colon adenocarcinoma cells labeled with [³⁵S]sulfate in the presence of these drug compounds. Cytosols of human lung, liver, kidney and small intestine were examined to verify the presence of 6-OH-Mel-, NAS- and 4-OH-Ram-sulfating activity in vivo. Of the four human organ samples tested, small intestine and liver cytosols displayed considerably higher 6-OH-Mel-, NAS- and 4-OH-Ram-sulfating activities than those of lung and kidney.

3. Collectively, these results provided a molecular basis for the metabolism of 6-OH-Mel, NAS and 4-OH-Ram through sulfation.

• N-Acetylserotonin
• 6-hydroxymelatonin
• 4-hydroxyramelteon
• sulfation
• SULT

Declaration of interest

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.