Mimnaugh E G, Trush M A, Gram T E
Biochem Pharmacol. 1986 Dec 1;35(23):4327-35. doi: 10.1016/0006-2952(86)90713-6.
Adriamycin causes both glomerular and tubular lesions in kidney, which can be severe enough to progress to irreversible renal failure. This drug-caused nephrotoxicity may result from the metabolic reductive activation of Adriamycin to a semiquinone free radical intermediate by oxidoreductive enzymes such as NADPH-cytochrome P-450 reductase and NADH-dehydrogenase. The drug semiquinone, in turn, autoxidizes and efficiently generates highly reactive and toxic oxyradicals. We report here that the reductive activation of Adriamycin markedly enhanced both NADPH- and NADH-dependent kidney microsomal membrane lipid peroxidation, measured as malonaldehyde by the thiobarbituric acid method. Adriamycin-enhanced kidney microsomal lipid peroxidation was diminished by the inclusion of the oxyradical scavengers, superoxide dismutase and 1,3-dimethylurea, and by the chelating agents, EDTA and diethylenetriamine-pentaacetic acid (DETPAC), implicating an obligatory role for reactive oxygen species and metal ions in the peroxidation mechanism. Furthermore, the inclusion of exogenous ferric and ferrous iron salts more than doubled Adriamycin-stimulated peroxidation. Lipid peroxidation was prevented by the sulfhydryl-reacting agent, p-chloromercuribenzenesulfonic acid, by omitting NAD(P)H, or by heat-inactivating the kidney microsomes, indicating the requirement for active pyridine-nucleotide linked enzymes. Several analogs of Adriamycin as well as mitomycin C, drugs which are capable of oxidation-reduction cycling, greatly increased NADPH-dependent kidney microsomal peroxidation. Carminomycin and 4-demethoxydaunorubicin were noteworthy in this respect because they were three to four times as potent as Adriamycin. In isolated kidney mitochondria, Adriamycin promoted a 12-fold increase in NADH-supported (NADH-dehydrogenase-dependent) peroxidation. These observations clearly indicate that anthracyclines enhance oxyradical-mediated membrane lipid peroxidation in vitro, and suggest that peroxidation-caused damage to kidney endoplasmic reticulum and mitochondrial membranes in vivo could contribute to the development of anthracycline-caused nephrotoxicity.
阿霉素可导致肾脏的肾小球和肾小管损伤，严重时可发展为不可逆的肾衰竭。这种药物引起的肾毒性可能是由于阿霉素通过氧化还原酶（如NADPH-细胞色素P-450还原酶和NADH-脱氢酶）代谢还原激活为半醌自由基中间体所致。反过来，药物半醌会自动氧化并有效产生高活性和有毒的氧自由基。我们在此报告，阿霉素的还原激活显著增强了NADPH和NADH依赖的肾脏微粒体膜脂质过氧化，通过硫代巴比妥酸法以丙二醛来衡量。阿霉素增强的肾脏微粒体脂质过氧化可通过加入氧自由基清除剂超氧化物歧化酶和1,3-二甲基脲，以及螯合剂EDTA和二乙烯三胺五乙酸（DETPAC）而减弱，这表明活性氧和金属离子在过氧化机制中起重要作用。此外，加入外源铁盐和亚铁盐使阿霉素刺激的过氧化增加了一倍多。脂质过氧化可通过巯基反应剂对氯汞苯磺酸、省略NAD(P)H或热灭活肾脏微粒体来防止，这表明需要有活性的吡啶核苷酸连接酶。阿霉素的几种类似物以及丝裂霉素C，这些能够进行氧化还原循环的药物，大大增加了NADPH依赖的肾脏微粒体过氧化。在这方面，卡米霉素和4-去甲氧基柔红霉素值得注意，因为它们的效力是阿霉素的三到四倍。在分离的肾脏线粒体中，阿霉素使NADH支持的（NADH-脱氢酶依赖的）过氧化增加了12倍。这些观察结果清楚地表明，蒽环类药物在体外增强了氧自由基介导的膜脂质过氧化，并表明过氧化导致的体内肾脏内质网和线粒体膜损伤可能促成了蒽环类药物引起的肾毒性的发展。
