Glutathione conjugation of busulfan produces a hydroxyl radical-trapping dehydroalanine metabolite.
Peer-CJ; Younis-IR; Leonard-SS; Gannett-PM; Minarchick-VC; Kenyon-AJ; Rojanasakul-Y; Callery-PS
Xenobiotica 2012 Dec; 42(12):1170-1177
1. The Phase 2 drug metabolism of busulfan yields a glutathione conjugate that undergoes a beta-elimination reaction. The elimination product is an electrophilic metabolite that is a dehydroalanine-containing tripeptide, gamma-glutamyldehydroalanylglycine (EdAG). In the process, glutathione lacks thiol-related redox properties and gains a radical scavenging dehydroalanine group. 2. EdAG scavenged hydroxyl radical generated in the Fenton reaction in a concentration-dependent manner was monitored by electron paramagnetic resonance (EPR) spectroscopy. The apparent rate of hydroxyl radical scavenging was in the same range as published values for known antioxidants, including N-acyl dehydroalanines. 3. A captodatively stabilized carbon-centered radical intermediate was spin trapped in the reaction of EdAG with hydroxyl radical. The proposed structure of a stable product in the Fenton reaction with EdAG was consistent with that of a gamma-glutamylserylglycyl dimer. 4. Observation of the hydroxyl trapping properties of EdAG suggests that the busulfan metabolite EdAG may contribute to or mitigate redox-related cytotoxicity associated with the therapeutic use of busulfan, and reaffirms indicators that support a role in free radical biology for dehydroalanine-containing peptides and proteins.
Drug-interaction; Drugs; Metabolites; Hydroxy-compounds; Hydroxyl-groups; Chemotherapy; Chemical-properties; Chemical-reactions; Chemical-structure; Antioxidants; Antineoplastic-agents; Peptides; Thiols; Oxidation-reduction-reactions; Free-radicals; Free-radical-generation; Electrochemical-analysis; Electrochemical-reactions; Spectrographic-analysis; Cytotoxicity; Therapeutic-agents; Proteins;
Author Keywords: Dehydroalanine; busulfan; metabolite; glutathione; hydroxyl radical; carbon-centered radical; EPR
Patrick S. Callery, School of Pharmacy, West Virginia University, 1 Medical Center Drive, Morgantown, WV 26506 USA