Hepatoprotective effect of ψ-glutathione in a murine model of acetaminophen-induced liver toxicity

Swati S. More, Jaime Nugent, Ashish P. Vartak, Steffan M. Nye, Robert Vince

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

Abstract

ψ-Glutathione (ψ-GSH) is an orally bioavailable and metabolism-resistant glutathione analogue that has been shown previously to substitute glutathione in most of its biochemical roles. Described here in its entirety is the preclinical evaluation of ψ-GSH as a rescue agent for acetaminophen (APAP) overdose: an event where time is of essence. By employing a murine model, four scenarios commonly encountered in emergency medicine are reconstructed. ψ-GSH is juxtaposed against N-acetylcysteine (NAC), the sole clinically available drug, in each of the scenarios. While both agents appear to be equally efficacious when timely administered, ψ-GSH partly retains its efficacy even in the face of substantial delay in administration. Thus, implied is the ability of ψ- GSH to intercept secondary toxicology following APAP insult. Oral availability and complete lack of toxicity as evaluated by liver function tests and survival analysis underscored ψ-GSH as a safer and more efficacious alternative to NAC. Finally, the pharmacodynamic mimicry of GSH by ψ-GSH is illustrated through the isolation and chemical characterization of an entity that can arise only through direct encounter of ψ-GSH with N-acetyl-p-benzoquinoneimine, the primary toxic metabolite of APAP.

Original languageEnglish (US)
Pages (from-to)777-784
Number of pages8
JournalChemical research in toxicology
Volume30
Issue number3
DOIs
StatePublished - Mar 20 2017

Bibliographical note

Publisher Copyright:
© 2017 American Chemical Society.

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