Peer Cody J, Younis Islam R, Leonard Stephen S, Gannett Peter M, Minarchick Valerie C, Kenyon Allison J, Rojanasakul Yon, Callery Patrick S
Department of Basic Pharmaceutical Sciences and Mary Babb Randolph Cancer Center, West Virginia University, Morgantown, WV 26506, USA.
Xenobiotica. 2012 Dec;42(12):1170-7. doi: 10.3109/00498254.2012.696740. Epub 2012 Jun 22.
The Phase 2 drug metabolism of busulfan yields a glutathione conjugate that undergoes a β-elimination reaction. The elimination product is an electrophilic metabolite that is a dehydroalanine-containing tripeptide, γ-glutamyldehydroalanylglycine (EdAG). In the process, glutathione lacks thiol-related redox properties and gains a radical scavenging dehydroalanine group. 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. 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 γ-glutamylserylglycyl dimer. 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.
白消安的2期药物代谢产生一种谷胱甘肽缀合物，该缀合物会发生β-消除反应。消除产物是一种亲电代谢物，即含脱氢丙氨酸的三肽，γ-谷氨酰脱氢丙氨酰甘氨酸（EdAG）。在此过程中，谷胱甘肽缺乏与硫醇相关的氧化还原特性，并获得一个清除自由基的脱氢丙氨酸基团。通过电子顺磁共振（EPR）光谱监测了EdAG以浓度依赖性方式清除芬顿反应中产生的羟基自由基的情况。羟基自由基清除的表观速率与已知抗氧化剂（包括N-酰基脱氢丙氨酸）的已发表值处于同一范围。在EdAG与羟基自由基的反应中，一个通过捕获稳定的碳中心自由基中间体被自旋捕获。在与EdAG的芬顿反应中提出的稳定产物结构与γ-谷氨酰丝氨酰甘氨酸二聚体的结构一致。对EdAG羟基捕获特性的观察表明，白消安代谢物EdAG可能有助于或减轻与白消安治疗用途相关的氧化还原相关细胞毒性，并重申了支持含脱氢丙氨酸的肽和蛋白质在自由基生物学中发挥作用的指标。
