title: 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.
authors.affiliation: a Department of Pharmacology , College of Pharmacy and Pharmaceutical Sciences, University of Toledo Health Science Campus , Toledo, OH , USA.|b School of Pharmacy , North Sichuan Medical College , Nanchong, Sichuan , China , and.
authors.forename: Lijun
authors.initials: L
authors.lastname: Luo
authors.affiliation: a Department of Pharmacology , College of Pharmacy and Pharmaceutical Sciences, University of Toledo Health Science Campus , Toledo, OH , USA.|b School of Pharmacy , North Sichuan Medical College , Nanchong, Sichuan , China , and.
authors.forename: Chunyang
authors.initials: C
authors.lastname: Zhou
authors.affiliation: c Department of Biochemistry and Applied Biosciences , University of Miyazaki , Miyazaki , Japan.
authors.forename: Katsuhisa
authors.initials: K
authors.lastname: Kurogi
authors.affiliation: c Department of Biochemistry and Applied Biosciences , University of Miyazaki , Miyazaki , Japan.
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Sakakibara
authors.affiliation: c Department of Biochemistry and Applied Biosciences , University of Miyazaki , Miyazaki , Japan.
authors.forename: Masahito
authors.initials: M
authors.lastname: Suiko
authors.affiliation: a Department of Pharmacology , College of Pharmacy and Pharmaceutical Sciences, University of Toledo Health Science Campus , Toledo, OH , USA.
authors.forename: Ming-Cheh
authors.initials: MC
authors.lastname: Liu
keywords: 4-hydroxyramelteon; 6-hydroxymelatonin; N-Acetylserotonin; SULT; sulfation