John Curtin School of Medical Research, Australian National University, PO Box 334, Canberra, ACT 2601, Australia.
Biochem Pharmacol. 2012 Feb 1;83(3):427-33. doi: 10.1016/j.bcp.2011.11.012. Epub 2011 Nov 23.
Dichloroacetic acid (DCA) has potential for use in cancer therapy and the treatment of metabolic acidosis. However, DCA can create a deficiency of glutathione transferase Zeta (GSTZ1-1). Gstz1 knockout mice have elevated oxidative stress and low glutathione levels that increases their sensitivity to acetaminophen toxicity. As it is highly likely that patients that are treated with DCA will develop drug induced GSTZ1-1 deficiency we considered they could be at risk of elevated toxicity if they are exposed to other drugs that cause oxidative stress or consume glutathione (GSH). To test this hypothesis we treated mice with DCA and acetaminophen (APAP). Surprisingly, the mice pre-treated with DCA suffered less APAP-mediated hepatotoxicity than untreated mice. This protection is most likely due to an increased capacity for the liver to synthesize GSH, since DCA increased the expression and activity of glutamate-cysteine ligase GCL, the rate-limiting enzyme of GSH synthesis. Other pathways for acetaminophen disposal were unchanged or diminished by DCA. Pre-treatment with DCA may be of use in other settings where the maintenance of protective levels of GSH are required. However, DCA may lower the efficacy of drugs that rely on oxidative stress and the depletion of GSH to enhance their cytotoxicity or of drugs that are detoxified by GSH conjugation. Consequently, as the use of DCA in the clinic is likely to increase, it will be critical to evaluate the interactions of DCA with other drugs to ensure the combinations retain their efficacy and do not cause enhanced toxicity.
二氯乙酸 (DCA) 具有在癌症治疗和代谢性酸中毒治疗中的应用潜力。然而，DCA 可能会导致谷胱甘肽转移酶 Zeta（GSTZ1-1）缺乏。Gstz1 敲除小鼠的氧化应激增加，谷胱甘肽水平降低，使其对乙酰氨基酚毒性的敏感性增加。由于接受 DCA 治疗的患者很可能会出现药物诱导的 GSTZ1-1 缺乏症，因此我们认为，如果他们接触到其他引起氧化应激或消耗谷胱甘肽（GSH）的药物，他们可能面临毒性升高的风险。为了验证这一假设，我们用 DCA 和对乙酰氨基酚（APAP）处理了小鼠。令人惊讶的是，用 DCA 预处理的小鼠比未处理的小鼠遭受的 APAP 介导的肝毒性要小。这种保护作用很可能是由于肝脏合成 GSH 的能力增加所致，因为 DCA 增加了 GSH 合成的限速酶谷氨酸半胱氨酸连接酶 GCL 的表达和活性。其他处理 APAP 的途径则不受 DCA 影响或减弱。DCA 的预处理可能在其他需要维持保护性 GSH 水平的情况下有用。然而，DCA 可能会降低依赖氧化应激和 GSH 耗竭来增强其细胞毒性的药物或通过 GSH 结合解毒的药物的疗效。因此，随着 DCA 在临床上的应用可能会增加，评估 DCA 与其他药物的相互作用以确保这些组合保留其疗效并避免增强毒性将至关重要。
