Human Sulfotransferases Enhance the Cytotoxicity of Tolvaptan

Toxicol Sci. 2016 Mar;150(1):27-39. doi: 10.1093/toxsci/kfv311. Epub 2015 Dec 10.


Tolvaptan, a vasopressin receptor 2 antagonist used to treat hyponatremia, has recently been reported to be associated with liver injury. Sulfotransferases (SULTs) have been implicated as important detoxifying and/or activating enzymes for numerous xenobiotics, drugs, and endogenous compounds. To characterize better the role of SULTs in tolvaptan metabolism, HEK293 cells stably overexpressing 12 human SULTs were generated. Using these cell lines, the extent of tolvaptan sulfate formation was assessed by reversed-phase high-performance liquid chromatography through comparison to a synthetic standard. Of the 12 known human SULTs, no detectable sulfation of tolvaptan was observed with SULT1A1, SULT1A2, SULT1A3, SULT1C2, SULT1C4, SULT4A1, or SULT6B1. The affinity of individual SULT isozymes, as determined by Km analysis, was SULT1C3 >> SULT2A1 > SULT2B1 ∼ SULT1B1 > SULT1E1. The half inhibitory concentration of tolvaptan on cell growth in HEK293/SULT1C3 cells and HEK293/CYP3A4 & SULT1C3 cells was significantly lower than that in the corresponding HEK293/vector cells or HEK293/CYP3A4 & SULT vector cells. Moreover, exposing cells to tolvaptan in the presence of cyclosporine A, an inhibitor of the drug efflux transporters, significantly increased the intracellular levels of tolvaptan sulfate and decreased the cell viability in HEK293/SULT1C3 cells. These data indicate that sulfation increased the cytotoxicity of tolvaptan.

Keywords: cytotoxicity; drug efflux transporters; metabolism; sulfation; tolvaptan.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Antidiuretic Hormone Receptor Antagonists / metabolism
  • Antidiuretic Hormone Receptor Antagonists / toxicity*
  • Benzazepines / metabolism
  • Benzazepines / toxicity*
  • Biotransformation
  • Blotting, Western
  • Cell Culture Techniques
  • Cell Survival / drug effects
  • Chromatography, High Pressure Liquid
  • Dose-Response Relationship, Drug
  • HEK293 Cells
  • Humans
  • Isoenzymes
  • Kinetics
  • Sulfotransferases / genetics
  • Sulfotransferases / metabolism*
  • Tolvaptan


  • Antidiuretic Hormone Receptor Antagonists
  • Benzazepines
  • Isoenzymes
  • Tolvaptan
  • Sulfotransferases