Pimstone N R, Engel P, Tenhunen R, Seitz P T, Marver H S, Schmid R
J Clin Invest. 1971 Oct;50(10):2042-50. doi: 10.1172/JCI106697.
We have recently identified and characterized NADPH-dependent microsomal heme oxygenase as the major enzymatic mechanism for the conversion of hemoglobin-heme to bilirubin-IXalpha in vivo. Enzyme activity is highest in tissues normally involved in red cell breakdown, that is, spleen, liver, and bone marrow, but it usually is negligible in the kidney. However, renal heme oxygenase activity may be transiently increased 30- to 100-fold following hemoglobinemia that exceeded the plasma haptoglobin-binding capacity and consequently resulted in hemoglobinuria. Maximal stimulation of enzyme activity in rats is reached 6-16 hr following a single intravenous injection of 30 mg of hemoglobin per 100 g body weight; activity returns to basal levels after about 48 hr. At peak level, total enzyme activity in the kidneys exceeds that of the spleen or liver. Cyclohexamide, puromycin, or actinomycin D, given just before, or within a few hours after, a single intravenous injection of hemoglobin minimizes or prevents the rise in renal enzyme activity; this suggests that the increase in enzyme activity is dependent on continued synthesis of ribonucleic acid and protein. The apparent biological half-life of renal heme oxygenase is about 6 hr. These observations indicate that functional adaptation of renal heme oxygenase activity reflects enzyme induction either directly or indirectly by the substrate, hemoglobin. Filtered rather than plasma hemoglobin appears to regulate renal heme oxygenase activity. Thus, stabilization of plasma hemoglobin in its tetrameric form with bis (N-maleimidomethyl) ether, which diminishes its glomerular filtration and retards it plasma clearance, results in reduced enzyme stimulation in the kidney, but enhances its activity in the liver. These findings suggest that the enzyme is localized in the tubular epithelial cells rather than in the glomeruli and is activated by luminal hemoglobin. Direct support for this concept was obtained by the demonstration of heme oxygenase activity in renal tubules isolated from rabbits that had been injected with hemoglobin.
我们最近已鉴定并表征了NADPH依赖性微粒体血红素加氧酶，它是体内血红蛋白-血红素转化为胆红素-IXα的主要酶促机制。酶活性在通常参与红细胞分解的组织中最高，即脾脏、肝脏和骨髓，但在肾脏中通常可忽略不计。然而，在血红蛋白血症超过血浆结合珠蛋白结合能力并因此导致血红蛋白尿后，肾脏血红素加氧酶活性可能会短暂增加30至100倍。在每100克体重单次静脉注射30毫克血红蛋白后6至16小时，大鼠的酶活性达到最大刺激；约48小时后活性恢复到基础水平。在峰值水平时，肾脏中的总酶活性超过脾脏或肝脏。在单次静脉注射血红蛋白之前或之后数小时内给予环己酰亚胺、嘌呤霉素或放线菌素D可使肾脏酶活性的升高最小化或阻止其升高；这表明酶活性的增加依赖于核糖核酸和蛋白质的持续合成。肾脏血红素加氧酶的表观生物学半衰期约为6小时。这些观察结果表明，肾脏血红素加氧酶活性的功能适应性反映了底物血红蛋白直接或间接诱导的酶诱导作用。滤过的而非血浆中的血红蛋白似乎调节肾脏血红素加氧酶活性。因此，用双（N-马来酰亚胺甲基）醚将血浆血红蛋白稳定在其四聚体形式，这会减少其肾小球滤过并延缓其血浆清除，导致肾脏中酶刺激减少，但增强其在肝脏中的活性。这些发现表明该酶定位于肾小管上皮细胞而非肾小球中，并被管腔内的血红蛋白激活。通过证明从注射了血红蛋白的兔子分离的肾小管中的血红素加氧酶活性，获得了对这一概念的直接支持。
