Drug toxicity profiling of a Saccharomyces cerevisiae deubiquitinase deletion panel shows that acetaminophen mimics tyrosine.

Abstract

Post-translational protein modification by addition or removal of the small polypeptide ubiquitin is involved in a range of critical cellular processes, like proteasomal protein degradation, DNA repair, gene expression, internalization of membrane proteins, and drug sensitivity. We recently identified genes important for acetaminophen (APAP) toxicity in a comprehensive screen and our findings suggested that a small set of yeast strains carrying deletions of ubiquitin-related genes can be informative for drug toxicity profiling. In yeast, approximately 20 different deubiquitinating enzymes (DUBs) have been identified, of which only one is essential for viability. We investigated whether the toxicity profile of DUB deletion yeast strains would be informative about the toxicological mode of action of APAP. A set of DUB deletion strains was tested for sensitivity and resistance to a diverse series of compounds, including APAP, quinine, ibuprofen, rapamycin, cycloheximide, cadmium, peroxide and amino acids and a cluster analysis was performed. Most DUB deletion strains showed an altered growth pattern when exposed to these compounds by being either more sensitive or more resistant than WT. Toxicity profiling of the DUB strains revealed a remarkable overlap between the amino acid tyrosine and acetaminophen (APAP), but not its stereoisomer AMAP. Furthermore, co-exposure of cells to both APAP and tyrosine showed an enhancement of the cellular growth inhibition, suggesting that APAP and tyrosine have a similar mode of action.

• Authors: Angelina Huseinovic, Marc van Dijk, Nico P E Vermeulen, Fred van Leeuwen, Jan M Kooter, J Chris Vos
• Journal: Toxicology in vitro : an international journal published in association with BIBRA (Toxicol In Vitro) Vol. 47 Pg. 259-268 (Mar 2018) ISSN: 1879-3177 [Electronic] England
• PMID: 29258884 (Publication Type: Journal Article)
• Copyright: Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

Chemical References

• Aminophenols
• Analgesics, Non-Narcotic
• Isoenzymes
• Acetaminophen
• Tyrosine
• Deubiquitinating Enzymes

Topics

• Acetaminophen (adverse effects, analogs & derivatives, chemistry)
• Aminophenols (adverse effects, chemistry)
• Analgesics, Non-Narcotic (adverse effects, chemistry)
• Cluster Analysis
• Deubiquitinating Enzymes (genetics, metabolism)
• Drug Resistance, Bacterial
• Gene Deletion
• Haploidy
• Isoenzymes (genetics, metabolism)
• Microbial Viability (drug effects)
• Molecular Structure
• Saccharomyces cerevisiae (drug effects, enzymology, genetics, growth & development)
• Stereoisomerism
• Toxicity Tests (methods)
• Tyrosine (analogs & derivatives, chemistry, metabolism)