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Interactions between oxaprozin glucuronide and human serum albumin
D S Wells1, F W Janssen, H W Ruelius
1Wyeth Laboratories, Philadelphia, PA 19101-8299.
Xenobiotica; the Fate of Foreign Compounds in Biological Systems
|December 1, 1987
Summary
Oxaprozin glucuronide undergoes complex reactions with human serum albumin (HSA), including acyl migration and covalent binding. A specific tyrosine residue in HSA
Area of Science:
- Biochemistry
- Pharmacology
- Drug Metabolism
Background:
- Oxaprozin glucuronide is a metabolite of the nonsteroidal anti-inflammatory drug oxaprozin.
- Human serum albumin (HSA) is a major drug-binding protein in plasma.
- Understanding drug-protein interactions is crucial for predicting drug efficacy and toxicity.
Purpose of the Study:
- To elucidate the reaction mechanisms between oxaprozin glucuronide and human serum albumin (HSA).
- To identify the specific binding site and amino acid residues involved in the interaction.
- To investigate the role of HSA's tyrosine residue in the covalent binding of oxaprozin.
Main Methods:
- Studied the interaction of oxaprozin glucuronide with HSA in vitro.
- Utilized competitive binding assays with known HSA ligands.
- Employed chemical modification of specific amino acid residues (tyrosine, lysine, cysteine) on HSA.
Main Results:
- Oxaprozin glucuronide forms a reversible complex with HSA, followed by acyl migration, hydrolysis, and covalent binding.
- Ligands binding to HSA's Site II (benzodiazepine site) inhibit these reactions.
- Modification of a tyrosine residue within Site II significantly reduced covalent binding, suggesting its nucleophilic role.
Conclusions:
- The interaction of oxaprozin glucuronide with HSA involves specific reactions at Site II, mediated by a tyrosine residue.
- HSA's tyrosine residue (tyr-411) acts as a nucleophile in the covalent binding of oxaprozin.
- These findings provide insights into the metabolic fate and protein binding of oxaprozin.