The University of Southampton
University of Southampton Institutional Repository

Chemistry, pharmacology and cellular uptake mechanisms of thiometallate sulfide donors

Chemistry, pharmacology and cellular uptake mechanisms of thiometallate sulfide donors
Chemistry, pharmacology and cellular uptake mechanisms of thiometallate sulfide donors

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.

0007-1188
Durham, Tom
b4a5b98f-dd23-466b-a2b0-55f8725232b4
Zander, David
91f242af-f76a-414e-b77b-334a1bf1e1f9
Stomeo, Niccolò
2e28b9a9-1cf1-4a41-9ab2-2e7a8d7a0116
Minnion, Magdalena
ab23b32b-9f8e-4876-aaf5-99cb6a725a2f
Hogarth, Graeme
f802556c-a430-4fd3-84c4-942a695227cd
Feelisch, Martin
8c1b9965-8614-4e85-b2c6-458a2e17eafd
Singer, Mervyn
87229716-c753-44ab-a382-3f93c1c5441d
Dyson, Alex
e288e219-cdac-4c63-85c6-9c2b6cdb194c
Durham, Tom
b4a5b98f-dd23-466b-a2b0-55f8725232b4
Zander, David
91f242af-f76a-414e-b77b-334a1bf1e1f9
Stomeo, Niccolò
2e28b9a9-1cf1-4a41-9ab2-2e7a8d7a0116
Minnion, Magdalena
ab23b32b-9f8e-4876-aaf5-99cb6a725a2f
Hogarth, Graeme
f802556c-a430-4fd3-84c4-942a695227cd
Feelisch, Martin
8c1b9965-8614-4e85-b2c6-458a2e17eafd
Singer, Mervyn
87229716-c753-44ab-a382-3f93c1c5441d
Dyson, Alex
e288e219-cdac-4c63-85c6-9c2b6cdb194c

Durham, Tom, Zander, David, Stomeo, Niccolò, Minnion, Magdalena, Hogarth, Graeme, Feelisch, Martin, Singer, Mervyn and Dyson, Alex (2019) Chemistry, pharmacology and cellular uptake mechanisms of thiometallate sulfide donors. British Journal of Pharmacology. (doi:10.1111/bph.14670).

Record type: Article

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.

Text
Durham_et_al-2019-British_Journal_of_Pharmacology - Accepted Manuscript
Restricted to Repository staff only until 29 March 2020.
Request a copy

More information

Accepted/In Press date: 10 March 2019
e-pub ahead of print date: 29 March 2019
Additional Information: This article is protected by copyright. All rights reserved.

Identifiers

Local EPrints ID: 430265
URI: https://eprints.soton.ac.uk/id/eprint/430265
ISSN: 0007-1188
PURE UUID: 3c8c4764-3f8b-4b8b-bd02-7a712091ab43
ORCID for Martin Feelisch: ORCID iD orcid.org/0000-0003-2320-1158

Catalogue record

Date deposited: 23 Apr 2019 16:30
Last modified: 24 Apr 2019 00:31

Export record

Altmetrics

Contributors

Author: Tom Durham
Author: David Zander
Author: Niccolò Stomeo
Author: Magdalena Minnion
Author: Graeme Hogarth
Author: Martin Feelisch ORCID iD
Author: Mervyn Singer
Author: Alex Dyson

University divisions

Download statistics

Downloads from ePrints over the past year. Other digital versions may also be available to download e.g. from the publisher's website.

View more statistics

Atom RSS 1.0 RSS 2.0

Contact ePrints Soton: eprints@soton.ac.uk

ePrints Soton supports OAI 2.0 with a base URL of https://eprints.soton.ac.uk/cgi/oai2

This repository has been built using EPrints software, developed at the University of Southampton, but available to everyone to use.

We use cookies to ensure that we give you the best experience on our website. If you continue without changing your settings, we will assume that you are happy to receive cookies on the University of Southampton website.

×