Parkes J G, Hussain R A, Olivieri N F, Templeton D M
Department of Clinical Biochemistry, University of Toronto, Ontario, Canada.
J Lab Clin Med. 1993 Jul;122(1):36-47.
Accumulation of Fe in the myocardium in circumstances of transferrin saturation is associated with heart failure in Fe-loaded patients. To characterize the underlying causes of this phenomenon, we measured the flux as well as the speciation of Fe in normal and Fe-loaded cultures of rat myocardiocytes. Fe loading with low-molecular-weight Fe (ferric ammonium citrate) promoted a dose- and time-dependent increase in the rate of uptake of non-transferrin-bound Fe (NTBI) that was positively correlated (R = 0.9, p < 0.005) with cellular iron content. At concentrations sufficient to produce this up-regulation, membrane integrity was unaffected but the rate of spontaneous beating of the cells was decreased by 60%. The enhanced rate of NTBI uptake in Fe-loaded cells reverted to control rates after treatment with therapeutic concentrations of Fe chelators deferoxamine, 1,2-dimethyl-3-hydroxypyrid-4-one and 1,2-diethyl-3-hydroxypyrid-4-one under conditions where approximately 80% of the cellular Fe was removed by chelation. Fe loading of cultured myocytes also induced shifts in Fe speciation. Thus the ratio of Fe bound in hemosiderin-like precipitates to ferritin-bound Fe increased twofold, from a range of 0.84 to 1.44 in control cells to 1.96 to 3.3 in iron-loaded cells. This increased ratio was similar to that measured in the heart and liver of a thalassemic patient who underwent a double transplant for the failure of both organs, even though the Fe content of the heart (mean, 5.8 mg Fe/gm dry weight) was much less than that of the liver (28.1 mg/gm dry weight). These results suggest that increased rates of uptake of NTBI may exacerbate iron loading of the heart and contribute to iron-mediated cardiotoxicity, whereas the clinical benefits of chelation therapy may be enhanced by the down-regulation of NTBI uptake.
转铁蛋白饱和情况下心肌中铁的蓄积与铁负荷患者的心力衰竭有关。为了阐明这一现象的潜在原因，我们测定了正常及铁负荷大鼠心肌细胞培养物中铁的通量和形态。用低分子量铁（柠檬酸铁铵）进行铁负荷促进了非转铁蛋白结合铁（NTBI）摄取速率呈剂量和时间依赖性增加，该摄取速率与细胞铁含量呈正相关（R = 0.9，p < 0.005）。在足以产生这种上调的浓度下，膜完整性未受影响，但细胞的自发搏动速率降低了60%。在用治疗浓度的铁螯合剂去铁胺、1,2 - 二甲基 - 3 - 羟基吡啶 - 4 - 酮和1,2 - 二乙基 - 3 - 羟基吡啶 - 4 - 酮处理后，铁负荷细胞中NTBI摄取增强的速率恢复到对照速率，在此条件下约80%的细胞铁通过螯合被去除。培养心肌细胞的铁负荷也诱导了铁形态的变化。因此，结合在类含铁血黄素沉淀物中的铁与结合在铁蛋白中的铁的比例增加了两倍，从对照细胞中的0.84至1.44增加到铁负荷细胞中的1.96至3.3。这种增加的比例与一名因两个器官衰竭而接受双重移植的地中海贫血患者的心脏和肝脏中测得的比例相似，尽管心脏的铁含量（平均5.8 mg铁/克干重）远低于肝脏（28.1 mg/克干重）。这些结果表明，NTBI摄取速率增加可能会加剧心脏的铁负荷并导致铁介导的心脏毒性，而螯合疗法的临床益处可能会因NTBI摄取的下调而增强。
