On the sulfation of O-desmethyltramadol by human cytosolic sulfotransferases

• Published in: Pharmacological reports Vol. 69; no. 5; pp. 953 - 958
• Main Authors: Rasool, Mohammed I., Bairam, Ahsan F., Kurogi, Katsuhisa, Liu, Ming-Cheh
• Format: Journal Article
• Language: English
• Published: Cham Elsevier Urban & Partner Sp. z o.o 01.10.2017; Springer International Publishing
• Subjects: Caco-2 Cells; Cytosol - enzymology; Cytosolic sulfotransferase; Drug Safety and Pharmacovigilance; Hep G2 Cells; Humans; Hydrogen-Ion Concentration; Intestine, Small - cytology; Kidney - cytology; Liver - cytology; Lung - cytology; Molecular Structure; O-Desmethyltramadol; Original Article; Pharmacotherapy; Pharmacy; Sulfation; Sulfotransferases - metabolism; SULT; Tramadol; Tramadol - analogs & derivatives; Tramadol - chemistry; Tramadol - metabolism; PAPS; Cytosolic sulfotransferase; O-DMT; Tramadol; O-Desmethyltramadol; TLC; ATP; SULT; Sulfation; Desmethyltramadol
• DOI: 10.1016/j.pharep.2017.02.014
• ISSN: 1734-1140

[Display omitted] Previous studies have demonstrated that sulfate conjugation is involved in the metabolism of the active metabolite of tramadol, O-desmethyltramadol (O-DMT). The current study aimed to systematically identify the human cytosolic sulfotransferases (SULTs) that are capable of mediating the sulfation of O-DMT. The sulfation of O-DMT under metabolic conditions was demonstrated using HepG2 hepatoma cells and Caco-2 human colon carcinoma cells. O-DMT-sulfating activity of thirteen known human SULTs and four human organ specimens was examined using an established sulfotransferase assay. pH-Dependency and kinetic parameters were also analyzed using, respectively, buffers at different pHs and varying O-DMT concentrations in the assays. Of the thirteen human SULTs tested, only SULT1A3 and SULT1C4 were found to display O-DMT-sulfating activity, with different pH-dependency profiles. Kinetic analysis revealed that SULT1C4 was 60 times more catalytically efficient in mediating the sulfation of O-DMT than SULT1A3 at respective optimal pH. Of the four human organ specimens tested, the cytosol prepared from the small intestine showed much higher O-DMT-sulfating activity than cytosols prepared from liver, lung, and kidney. Both cultured HepG2 and Caco-2 cells were shown to be capable of sulfating O-DMT and releasing sulfated O-DMT into cultured media. SULT1A3 and SULT1C4 were the major SULTs responsible for the sulfation of O-DMT. Collectively, the results obtained provided a molecular basis underlying the sulfation of O-DMT and contributed to a better understanding about the pharmacokinetics and pharmacodynamics of tramadol in humans.