Wright T L, Brissot P, Ma W L, Weisiger R A
J Biol Chem. 1986 Aug 15;261(23):10909-14.
Recent evidence suggests that the hepatic iron-loading characteristic of hemochromatosis may result in part from efficient hepatic clearance of non-transferrin-bound iron, which is increased in this disorder. However, this hypothesis assumes that hepatic clearance remains highly efficient despite excess iron stores. We therefore studied hepatic uptake of non-transferrin-bound iron in the single-pass perfused rat liver under varying conditions. Animals were iron loaded or depleted by dietary manipulation, but no changes in the efficiency of ferrous iron uptake or the kinetic parameters were seen (single-pass extraction, 59-74%; Km, 16-19 microM; Vmax, 30-32 nmol X min-1 X g liver-1). Added divalent zinc, cobalt, and manganese ions reversibly inhibited ferrous iron uptake and the inhibition by zinc was shown to be competitive. Uptake required calcium, was markedly temperature-sensitive (delta E = 14.3 Kcal/mol), and was relatively insensitive to inhibition of cellular energy metabolism. Particles consistent with ferritin cores were seen in lysosomes of hepatic parenchymal cells within 30 min of perfusion with ferrous iron. These results suggest that ferrous iron is cleared from plasma by a passive, saturable transport process that is not regulated by the iron content of the liver and that may be shared with other transition metal ions. Because clearance is highly efficient, increased levels of non-transferrin-bound iron in plasma may present the liver with an obligatory iron load resulting in progressive accumulation and toxicity.
近期证据表明，血色素沉着症的肝脏铁负荷特征可能部分源于肝脏对非转铁蛋白结合铁的高效清除，而在这种病症中该清除作用会增强。然而，这一假说假定尽管铁储存过量，肝脏清除仍保持高效。因此，我们研究了在不同条件下单次灌注大鼠肝脏对非转铁蛋白结合铁的摄取情况。通过饮食调控使动物铁负荷增加或降低，但亚铁摄取效率或动力学参数未见变化（单次提取率为59 - 74%；米氏常数为16 - 19微摩尔；最大反应速度为30 - 32纳摩尔·分钟⁻¹·克肝脏⁻¹）。添加的二价锌、钴和锰离子可逆性抑制亚铁摄取，且锌的抑制作用表现为竞争性。摄取需要钙，对温度极为敏感（活化能为14.3千卡/摩尔），且对细胞能量代谢抑制相对不敏感。在用亚铁灌注30分钟内，在肝实质细胞的溶酶体中可见与铁蛋白核心一致的颗粒。这些结果表明，亚铁通过一种被动的、可饱和的转运过程从血浆中清除，该过程不受肝脏铁含量调节，且可能与其他过渡金属离子共用。由于清除效率很高，血浆中非转铁蛋白结合铁水平升高可能给肝脏带来必然的铁负荷，导致铁逐渐蓄积并产生毒性。
