4-甲氧基邻苯醌的反应动力学及其细胞毒性机制：脉冲辐解研究

Reaction kinetics of 4-methoxy ortho benzoquinone in relation to its mechanism of cytotoxicity: a pulse radiolysis study.

作者信息

Land E J, Cooksey C J, Riley P A

机构信息

Paterson Institute for Cancer Research, Christie Hospital and Holt Radium Institute, Manchester, U.K.

出版信息

Biochem Pharmacol. 1990 Mar 15;39(6):1133-5. doi: 10.1016/0006-2952(90)90294-u.

DOI:10.1016/0006-2952(90)90294-u

PMID:2322299

Abstract

Rate constants quantifying the reactivity of 4-methoxy ortho benzoquinone, formed in the metabolic activation of 4-hydroxyanisole, a possible melanocytotoxic drug under current assessment as a treatment for malignant melanoma, have been determined by pulse radiolysis. The quinone is reactive towards the thiols cysteine (k = 3.5x10(5)M-1sec-1), glutathione (k = 3.1x10(5)M-1sec-1) and dithiothreitol (k = 3.5x10(5)M-1sec-1), but relatively unreactive towards other nucleophiles such as arginine (k less than or equal to 1M-1sec-1) and glutamine (k less than or equal to 1M-1sec-1). Redox exchange with ascorbate also occurs (k = 1.0x10(4)M-1sec-1). In view of the low reactivity of 4-methoxy ortho benzosemiquinone towards oxygen (k less than or equal to 10(5)M-1sec-1) and the model lipid trans-2-butenoic acid (k less than or equal to 2x10(5)M-1sec-1), it is unlikely that initiation of lipid peroxidation by the semiquinone is a major source of cytotoxicity. A more likely toxicity pathway appears to be covalent addition reactions of 4-methoxy ortho benzoquinone with cellular nucleophiles, especially thiols, and/or redox exchange reactions of the quinone leading to antioxidant depletion.

摘要

4-羟基苯甲醚在代谢活化过程中会形成4-甲氧基邻苯醌，目前它作为一种治疗恶性黑色素瘤的潜在黑素细胞毒性药物正在评估中。通过脉冲辐解已测定了量化该醌反应活性的速率常数。该醌与半胱氨酸（k = 3.5×10⁵M⁻¹s⁻¹）、谷胱甘肽（k = 3.1×10⁵M⁻¹s⁻¹）和二硫苏糖醇（k = 3.5×10⁵M⁻¹s⁻¹）等硫醇反应，但对精氨酸（k≤1M⁻¹s⁻¹）和谷氨酰胺（k≤1M⁻¹s⁻¹）等其他亲核试剂反应相对较弱。与抗坏血酸也会发生氧化还原交换（k = 1.0×10⁴M⁻¹s⁻¹）。鉴于4-甲氧基邻苯半醌对氧气（k≤10⁵M⁻¹s⁻¹）和模型脂质反式-2-丁烯酸（k≤2×10⁵M⁻¹s⁻¹）的反应活性较低，半醌引发脂质过氧化不太可能是细胞毒性的主要来源。更可能的毒性途径似乎是4-甲氧基邻苯醌与细胞亲核试剂，尤其是硫醇的共价加成反应，和/或醌的氧化还原交换反应导致抗氧化剂耗竭。