Powell S R, McCay P B
Department of Surgery, North Shore University Hospital-Cornell University Medical School, Manhasset, NY, USA.
Free Radic Biol Med. 1995 Feb;18(2):159-68. doi: 10.1016/0891-5849(94)00109-w.
The hypothesis was tested that glutathione exerts its protective actions against doxorubicin-induced oxidative stress through an enzyme-dependent mechanism. Glutathione at biological concentrations decreased doxorubicin-dependent rat hepatic microsomal lipid peroxidation, whereas N-acetylcysteine had no effect. Glutathione was utilized during this inhibition at a rate dependent on the concentration of both doxorubicin and the sulfhydryl. Increasing glutathione concentrations resulted in significant increases in utilization. N-acetylcysteine was also oxidized in the microsomal system; however, the rate of oxidation was not enhanced by doxorubicin. If bovine cardiac microsomes were substituted for the hepatic microsomes, no lipid peroxidation was detected in the presence of doxorubicin, yet significant utilization of glutathione was detected. Microsomes isolated from tocopherol-deficient rats utilized less glutathione in the presence of doxorubicin, and there was no inhibition of doxorubicin-dependent lipid peroxidation. These findings support the conclusion that glutathione inhibits hepatic microsomal lipid peroxidation initiated by the redox-cycling of doxorubicin. Inhibition of doxorubicin-dependent lipid peroxidation appears to be enzyme-mediated and to require tocopherol. A similar mechanism for protection against doxorubicin appears to be present in heart microsomal membranes.
研究了谷胱甘肽是否通过一种酶依赖性机制对阿霉素诱导的氧化应激发挥保护作用这一假说。生物浓度的谷胱甘肽可降低阿霉素依赖的大鼠肝微粒体脂质过氧化，而N-乙酰半胱氨酸则无此作用。在此抑制过程中，谷胱甘肽的利用速率取决于阿霉素和巯基的浓度。谷胱甘肽浓度增加导致利用显著增加。N-乙酰半胱氨酸在微粒体系统中也被氧化；然而，阿霉素并未提高其氧化速率。若用牛心脏微粒体替代肝微粒体，在有阿霉素存在的情况下未检测到脂质过氧化，但检测到谷胱甘肽有显著利用。从缺乏生育酚的大鼠分离出的微粒体在有阿霉素存在时利用的谷胱甘肽较少，且阿霉素依赖的脂质过氧化未受抑制。这些发现支持了谷胱甘肽抑制由阿霉素氧化还原循环引发的肝微粒体脂质过氧化这一结论。阿霉素依赖的脂质过氧化抑制似乎是由酶介导的，且需要生育酚。心脏微粒体膜中似乎也存在类似的抗阿霉素保护机制。
