Related Experiment Video

Updated: May 23, 2025

Spectrophotometric Screening for Potential Inhibitors of Cytosolic Glutathione S-Transferases
14:57

Spectrophotometric Screening for Potential Inhibitors of Cytosolic Glutathione S-Transferases

Published on: October 10, 2020

14.3K

Bioactivation of the β-Amyloid Precursor Protein-Cleaving Enzyme 1 Inhibitor Atabecestat Leads to Protein Adduct

Megan Ford1, Paul J Thomson1, Adam Lister1

  • 1Department Pharmacology and Therapeutics, University of Liverpool, Liverpool L693GE, U.K.

Chemical Research in Toxicology
|May 6, 2025
PubMed

Insights

Atabecestat exposure causes liver injury, leading to its withdrawal. This study found atabecestat forms adducts with proteins like GSTP, but only after bioactivation, suggesting a role in immune-mediated liver injury.

Area of Science:

  • Drug-induced liver injury
  • Chemical immunology
  • Proteomics

Background:

  • Atabecestat (a drug) was withdrawn due to liver injury.
  • Immune-mediated mechanisms are implicated in atabecestat-induced liver injury.
  • Irreversible protein modification is a suspected driver of drug immunogenicity.

Purpose of the Study:

  • To investigate the potential for atabecestat to form protein adducts.
  • To characterize adduct formation using human serum albumin (HSA), glutathione S-transferase alpha 1 (GSTA1), and glutathione S-transferase pi (GSTP) as model proteins.
  • To explore the role of bioactivation in atabecestat-protein adduct formation.

Main Methods:

  • Incubation of atabecestat with model proteins (HSA, GSTA1, GSTP) in the presence of metabolic systems.
  • Analysis of protein adduct formation using mass spectrometry-based techniques.

Main Results:

  • Atabecestat formed a covalent adduct specifically with a cysteine residue on GSTP.
  • Adduct formation was dependent on metabolic activation of atabecestat.
  • No adducts were observed with HSA or GSTA1 under the tested conditions.

Conclusions:

  • Bioactivation of atabecestat is crucial for its covalent binding to proteins.
  • The formation of atabecestat-GSTP adducts highlights the role of specific protein targets and metabolic pathways in drug immunogenicity.
  • These findings provide insights into the mechanisms underlying atabecestat-induced liver injury.

More Related Videos

Formation of Covalent DNA Adducts by Enzymatically Activated Carcinogens and Drugs In Vitro and Their Determination by 32P-postlabeling09:33

Formation of Covalent DNA Adducts by Enzymatically Activated Carcinogens and Drugs In Vitro and Their Determination by 32P-postlabeling

Published on: March 20, 2018

13.8K
Biotinylated Cell-penetrating Peptides to Study Intracellular Protein-protein Interactions10:26

Biotinylated Cell-penetrating Peptides to Study Intracellular Protein-protein Interactions

Published on: December 20, 2017

9.4K

Related Concept Videos

Phase II Reactions: Glutathione Conjugation and Mercapturic Acid Formation01:22

Phase II Reactions: Glutathione Conjugation and Mercapturic Acid Formation

Glutathione, a tripeptide made up of glutamate, cysteine, and glycine, is a critical player in the detoxification of drugs and xenobiotics via a process known as glutathione conjugation or mercapturic acid formation. This phase II biotransformation reaction involves the covalent binding of glutathione to a drug or its metabolite, enhancing the compound's water solubility and enabling its excretion.
Several distinctive characteristics distinguish glutathione conjugation from other phase II...
129
Phase II Reactions: Sulfation and Conjugation with α-Amino Acids01:19

Phase II Reactions: Sulfation and Conjugation with α-Amino Acids

Sulfation and α-amino acid conjugation are two critical biotransformation reactions in drug metabolism. Sulfation, a phase II biotransformation reaction, involves adding a polar sulfate group to a drug, enhancing its water solubility and promoting excretion. This process can either co-occur with or occur independently of glucuronidation. Nonmicrosomal sulfotransferase enzymes catalyze the process. The reaction involves 3'-phosphoadenosine-5'-phosphosulfate or PAPS coenzyme...
146
Drug Metabolism: Phase II Reactions01:14

Drug Metabolism: Phase II Reactions

Phase II reactions are essential for the detoxification and elimination of drugs from the body. These reactions involve the conjugation of parent drugs or their phase I metabolites with endogenous molecules, resulting in more hydrophilic drug conjugates. The primary conjugation reactions in this phase are sulfation and glucuronidation. Both sulfation and glucuronidation typically produce biologically inactive metabolites. However, in some cases involving prodrugs, active metabolites may be...
3.5K
Allosteric Proteins-ATCase01:19

Allosteric Proteins-ATCase

Binding sites linkages can regulate a protein's function.  For example, enzyme activity is often regulated through a feedback mechanism where the end product of the biochemical process serves as an inhibitor.
Aspartate transcarbamoylase (ATCase) is a cytosolic enzyme that catalyzes the condensation of L-aspartate and carbamoyl phosphate to  N-carbamoyl-L-aspartate. This reaction is the first step in pyrimidine biosynthesis. UTP and CTP, the end products of the pyrimidine synthesis...
5.6K
Phase II Reactions: Glucuronidation01:24

Phase II Reactions: Glucuronidation

Glucuronidation, a pivotal phase II biotransformation process, involves the coupling of glucuronic acid to a drug or xenobiotic. Given its widespread occurrence and critical role in drug metabolism, it's considered the most crucial phase II reaction. It enhances the water solubility of substances, aiding their expulsion from the body. The driving force behind these reactions is a group of enzymes known as UDP-glucuronosyltransferases (UGTs). UGTs facilitate the transfer of a glucuronic acid...
223
Phase II Reactions: Acetylation Reactions01:24

Phase II Reactions: Acetylation Reactions

Acetylation, a phase II biotransformation reaction, introduces an acetyl group to drugs or their metabolites. Acetyltransferase enzymes facilitate this reaction, which resembles α-amino acid conjugation due to the addition of a functional group to the drug molecule.
The substrates for acetylation are typically drugs or their metabolites with an amino, sulfonamide, or hydrazine functional group. Acetylation can occur at several points in the drug molecule, including primary, secondary, and...
157