Glutathione transferase deficient mice to probe for adverse drug reactions

代谢外来化学物质和治疗药物的称为谷胱甘肽转移酶（GST）的酶家族已被证明是癌症化疗中耐药性的重要原因。研究表明，GST抑制剂可用于癌症治疗，以对抗耐药性或减缓某些药物的代谢并增强其活性。一些GST与内源性底物进行重要的酶促反应，其他GST具有重要的非酶促功能，例如调节细胞内的信号传导途径和调节参与肌肉收缩的钙离子通道。因此，所有GST的一般抑制可能具有显著的不良生理效应。我们建议使小鼠缺乏特定的GST，并研究其生理反应。这些研究的结果将表明哪些GST可以被安全地抑制而没有有害副作用的风险。这些研究很重要，因为治疗药物的不良反应是住院和死亡的重要原因。

A family of enzymes called glutathione transferases (GST) that metabolize foreign chemicals and therapeutic drugs have been shown to be a significant cause of drug resistance in cancer chemotherapy. It has been suggested that inhibitors of GSTs could be used in cancer treatment to counter drug resistance or to slow the metabolism and enhance the activity of some drugs. Some GSTs carryout important enzymatic reactions with endogenous substrates and others have important non-enzymatic functions such as the regulation of signaling pathways within cells and the modulation of calcium ion channels that are involved in muscle contractions. The generic inhibition of all GSTs could therefore have significant adverse physiological effects. We propose to make mice deficient in specific GSTs and to study their physiological responses. The results of these studies will indicate which GSTs can be safely inhibited without the risk of deleterious side effects. These studies are important because adverse reactions to therapeutic drugs are a significant cause of hospital admissions and death.