BIOCHEMISTRY OF REDUCTION OF NITRO HETEROCYCLES
BIOCHEMISTRY OF REDUCTION OF NITRO HETEROCYCLES
复制标题
DOI：
10.1016/0006-2952(86)90561-7
复制
发表时间：
1986-01-01
影响因子：
5.8
通讯作者：
HALL, EJ
中科院分区：
文献类型：
--
作者：
BIAGLOW, JE;VARNES, ME;HALL, EJ
米索硝唑是一种代谢活性药物。将其添加到细胞中会立即改变细胞电子传递途径。在有氧条件下，代谢改变可能导致电子转移到氧气并产生过氧化物的无效循环。硫醇水平对于保护细胞免受过氧化物形成和羟基自由基产生的潜在危险条件极其重要。然而，这种电子分流出细胞代谢将导致戊糖循环、糖酵解和细胞能力的改变，以将代谢物还原为DNA代谢所需的必需中间体（即脱氧核糖核苷酸）。在米索硝唑和其他硝基化合物的毒性作用通过过氧化损伤导致细胞死亡之前，谷胱甘肽必须消耗到非常低的水平。在缺氧条件下，米索硝唑还通过其自身的还原作用来改变戊糖循环。然而，与有氧条件不同的是，会产生许多还原中间体，它们与非蛋白质硫醇（如谷胱甘肽）以及蛋白质硫醇发生反应。与蛋白质硫醇的反应导致糖酵解和其他尚未确定的酶系统的抑制。用硝基化合物对细胞进行缺氧预处理的后果是增加了对辐射和化疗药物（如 L-PAM、顺铂和博莱霉素）的脆弱性。酶活性的改变在细胞对米索硝唑和化疗药物的反应中所起的作用仍有待确定。同样清楚的是，谷胱甘肽耗尽状态不仅使细胞更容易受到氧化应激的影响，而且还容易受到米索硝唑还原超出单电子阶段而产生的缺氧中间体的影响。目前的工作与建议使用体内硫醇消耗来增强肿瘤组织的放射或化疗反应的相关性在于以下考虑。显然，当 GSH 消耗达到对照值的 10-20% 时，可能会对肝脏等正常组织产生自发性过氧化损伤；当 GSH 消耗达到对照值的 50% 时，也会对其他正常组织产生自发性过氧化损伤。如果使用产生过氧化物的药物，这种情况显然会变得更加严重。这种联合药物治疗的唯一优势在于肿瘤的过氧化氢酶和过氧化物酶活性可能有所不同，因此可能更容易受到氧化应激的影响（参见Meister的评论。我们的肿瘤模型，体外A549人肺癌细胞，似乎是一个例外，因为它具有过氧化氢酶，过氧化物酶和高含量的GSH。（摘要截断为400字）
Misonidazole is a metabolically active drug. Its addition to cells causes an immediate alteration in cellular electron transfer pathways. Under aerobic conditions the metabolic alterations can result in futile cycling with electron transfer to oxygen and production of peroxide. Thiol levels are extremely important in protecting the cell against the peroxide formation and potentially hazardous conditions for hydroxyl radical production. Nevertheless such electron shunting out of cellular metabolism will result in alterations in pentose cycle, glycolysis and cellular capacity to reduce metabolites to essential intermediates needed in DNA metabolism (ie deoxyribonucleotides). Glutathione must be depleted to very low levels before toxic effects of misonidazole and other nitro compounds are manifested in cell death via peroxidative damage. Under hypoxic conditions misonidazole also diverts the pentose cycle via its own reduction; however, unlike the aerobic conditions, there are a number of reductive intermediates produced that react with non-protein thiols such as GSH as well as protein thiols. The reaction with protein thiols results in the inhibition of glycolysis and other as yet undetermined enzyme systems. The consequences of the hypoxic pretreatment of cells with nitro compounds are increased vulnerability to radiation and chemotherapeutic drugs such as L-PAM, cis-platinum and bleomycin. The role that altered enzyme activity has in the cellular response to misonidazole and chemotherapeutic agents remains to be determined. It is also clear that the GSH depleted state not only makes cells more vulnerable to oxidative stress but also to hypoxic intermediates produced by the reduction of misonidazole beyond the one electron stage. The relevancy of the present work to the proposed use of thiol depletion in vivo to enhance the radiation or chemotherapeutic response of tumor tissue lies with the following considerations. Apparently, spontaneous peroxidative damage to normal tissue such as liver can occur with GSH depletion to 10-20% of control and with other normal tissue when GSH reaches 50% of control. This situation can obviously become more critical if peroxide producing drugs are administered. The only advantage to such combined drug treatments would lie in the possibility that tumors vary in their catalase and peroxidase activity and consequently may be more vulnerable to oxidative stress (cf. review by Meister. Our tumor model, the A549 human lung carcinoma cell in vitro, appears to be an exception because it has catalase, peroxidase and a high content of GSH.(ABSTRACT TRUNCATED AT 400 WORDS)