Chemistry, pharmacology and cellular uptake mechanisms of thiometallate sulfide donors

Abstract

BACKGROUND AND PURPOSE: A clinical need exists for targeted, safe and effective sulfide donors. We recently reported that ammonium tetrathiomolybdate (ATTM) belongs to a new class of sulfide-releasing drugs. Here, we investigate cellular uptake mechanisms of this drug class compared to sodium hydrosulfide (NaHS), and report on the thiometallate tungsten congener of ATTM, ammonium tetrathiotungstate (ATTT).

EXPERIMENTAL APPROACH: In vitro H2 S release was determined by head-space gas sampling of vials containing dissolved thiometallates. Thiometallate and NaHS bioactivity was assessed by spectrophotometry-derived sulfhaemoglobin formation. Cellular uptake dependence on the anion exchanger (AE)-1 was investigated in human red blood cells. ATTM/glutathione interactions were assessed by LC-MS/MS. Rodent pharmacokinetic and pharmacodynamic studies focussed on haemodynamics and inhibition of aerobic respiration.

KEY RESULTS: ATTM and ATTT both exhibit temperature-, pH-, and thiol-dependence of sulfide release. ATTM/glutathione interactions revealed the generation of inorganic and organic persulfides and polysulfides. ATTM showed greater ex vivo and in vivo bioactivity over ATTT, notwithstanding similar pharmacokinetic profiles. Cellular uptake mechanisms of the two drug classes are distinct; thiometallates show dependence on the AE-1 channel, while hydrosulfide itself was unaffected by inhibition of this pathway.

CONCLUSION AND IMPLICATIONS: Our demonstration that cellular uptake of thiometallates relies upon a plasma membrane ion channel advances our pharmacological knowledge of this drug class. It further supports their utility as cell-targeted sulfide donor therapies. Our results indicate that, as a more stable form, ATTT is better suited as a copper chelator. ATTM, a superior sulfide donor, may additionally participate in intracellular redox recycling.

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