Department of Medicine, Division of Endocrinology and Metabolism, College of Medicine, University of Florida, Gainesville, FL 32610, USA.
J Clin Pharmacol. 2012 Jun;52(6):837-49. doi: 10.1177/0091270011405664. Epub 2011 Jun 3.
Dichloroacetate (DCA), a chemical relevant to environmental science and allopathic medicine, is dehalogenated by the bifunctional enzyme glutathione transferase zeta (GSTz1)/maleylacetoacetate isomerase (MAAI), the penultimate enzyme in the phenylalanine/tyrosine catabolic pathway. The authors postulated that polymorphisms in GSTz1/MAAI modify the toxicokinetics of DCA. GSTz1/MAAI haplotype significantly affected the kinetics and biotransformation of 1,2-¹³C-DCA when it was administered at either environmentally (µg/kg/d) or clinically (mg/kg/d) relevant doses. GSTz1/MAAI haplotype also influenced the urinary accumulation of potentially toxic tyrosine metabolites. Atomic modeling revealed that GSTz1/MAAI variants associated with the slowest rates of DCA metabolism induced structural changes in the enzyme homodimer, predicting protein instability or abnormal protein-protein interactions. Knowledge of the GSTz1/MAAI haplotype can be used prospectively to identify individuals at potential risk of DCA's adverse side effects from environmental or clinical exposure or who may exhibit aberrant amino acid metabolism in response to dietary protein.
二氯乙酸（DCA）是一种与环境科学和对抗疗法医学相关的化学物质，它由双功能酶谷胱甘肽转移酶 ζ（GSTz1）/马来酰乙酰乙酸异构酶（MAAI）脱卤，该酶是苯丙氨酸/酪氨酸分解代谢途径中的最后一个酶。作者假设 GSTz1/MAAI 多态性改变了 DCA 的毒代动力学。当以环境相关剂量（µg/kg/d）或临床相关剂量（mg/kg/d）给予 GSTz1/MAAI 单倍型时，它对 1,2-¹³C-DCA 的动力学和生物转化有显著影响。GSTz1/MAAI 单倍型还影响潜在毒性酪氨酸代谢物的尿中积累。原子建模表明，与 DCA 代谢最慢速率相关的 GSTz1/MAAI 变体诱导酶同二聚体的结构变化，预测蛋白质不稳定性或异常蛋白质-蛋白质相互作用。GSTz1/MAAI 单倍型的知识可以前瞻性地用于识别那些可能因环境或临床暴露而面临 DCA 不良反应风险的个体，或那些可能表现出异常氨基酸代谢以响应膳食蛋白质的个体。
