Barnabé Norman, Marusak Rosemary A, Hasinoff Brian B
Faculty of Pharmacy, University of Manitoba, Winnipeg, Manitoba, Canada R3T 2N2.
Nitric Oxide. 2003 Dec;9(4):211-6. doi: 10.1016/j.niox.2003.12.001.
The clinical use of the widely used anticancer drug doxorubicin is limited by a dose-dependent cardiotoxicity. Doxorubicin can be reduced to its semiquinone free radical form by nitric oxide synthases (NOS). The release of lactate dehydrogenase (LDH) from doxorubicin-treated neonatal cardiac rat myocytes was used as a model of doxorubicin-induced cardiotoxicity. The NOS inhibitors N(G)-nitro-L-arginine methyl ester (L-NAME) and N(G)-monomethyl-L-arginine (L-NMMA) protected myocytes from doxorubicin as did their non-inhibitory enantiomers D-NAME and D-NMMA. Thus, these agents did not protect by inhibiting NOS. L-NAME, which does not act at the reductase domain of NOS, also had no effect on the production of the doxorubicin semiquinone by myocytes. Nitric oxide (NO) EPR spin trapping experiments showed that L-NAME reacted with various biological reducing agents to produce NO. Ascorbic acid was highly effective in reacting with L-NAME to produce NO, while glutathione, NADPH, and NADH were much less effective. Thus, these guanadino-substituted analogs of L-arginine likely protected through their ability to slowly produce NO by reaction with intracellular ascorbic acid. Thus, some caution must be exercised in their use. NO may exert its protective effects either by directly acting as an antioxidant or through some other NO-dependent pathway.
广泛使用的抗癌药物阿霉素的临床应用受到剂量依赖性心脏毒性的限制。阿霉素可被一氧化氮合酶（NOS）还原为半醌自由基形式。用阿霉素处理新生大鼠心肌细胞后乳酸脱氢酶（LDH）的释放被用作阿霉素诱导的心脏毒性模型。NOS抑制剂N（G）-硝基-L-精氨酸甲酯（L-NAME）和N（G）-单甲基-L-精氨酸（L-NMMA）对阿霉素处理的心肌细胞具有保护作用，它们的非抑制性对映体D-NAME和D-NMMA也有同样的作用。因此，这些药物不是通过抑制NOS起到保护作用。不作用于NOS还原酶结构域的L-NAME对心肌细胞产生阿霉素半醌也没有影响。一氧化氮（NO）电子顺磁共振自旋捕集实验表明，L-NAME与各种生物还原剂反应生成NO。抗坏血酸与L-NAME反应生成NO的效率很高，而谷胱甘肽、NADPH和NADH的效率则低得多。因此，这些L-精氨酸的胍基取代类似物可能通过与细胞内抗坏血酸反应缓慢产生NO的能力起到保护作用。因此，在使用它们时必须谨慎。NO可能通过直接作为抗氧化剂或通过其他一些依赖NO的途径发挥其保护作用。
