On the sulfation of O-desmethyltramadol by human cytosolic sulfotransferases

Background 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. methods 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. results 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. conclusion 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. © 2017 institute of pharmacology,polish academy of sciences