Qato M K, Maines M D
Biochem J. 1985 Feb 15;226(1):51-7. doi: 10.1042/bj2260051.
Non-human primates were used as a model of human neonatal hyperbilirubinaemia and its chemotherapeutic suppression. High levels of haem oxygenase activity were detected in the liver and the spleen of neonatal rhesus (Macaca mulatta) and cynomolgus (Macaca irus) monkeys. When 1-day-old neonatal animals were given a single injection of Zn-protoporphyrin (40 mumol/kg, subcutaneously), serum bilirubin levels declined to nearly normal adult levels within 24 h and remained suppressed throughout the postnatal period (12 days). This treatment inhibited the activities of haem oxygenase and biliverdin reductase in the liver and the spleen, without affecting that of the brain. Zn-protoporphyrin treatment did not alter the activity of brain biliverdin reductase or increase brain bilirubin levels. The biological disposition of Zn-protoporphyrin was examined by measuring the biliary and urinary excretion of the metalloporphyrin complex, as well as its uptake and deposition in blood cells and tissues. Biliary excretion of the metalloporphyrin was minimal (0.12% over a 28 h period), and no evidence was detected for the urinary excretion of Zn-protoporphyrin. However, the concentration of metalloporphyrin in erythrocytes increased over the duration of the experiment (11 days) to such an extent that 46% of the administered compound was taken up by the cells. It appeared that the molecular basis for the sustained suppression of haem oxygenase activity and bilirubin production by Zn-protoporphyrin involved the release of the metalloporphyrin in the normal process of the degradation of fetal erythrocytes. The scope of the biological activity of Zn-protoporphyrin to alter haem-dependent processes appeared limited in nature, insofar as the microsomal contents of cytochrome P-450 and b5, as well as the aniline hydroxylase, were similar to those of the control animals. Also, the concentration of glutathione in the liver was unchanged. These findings suggest the potential usefulness of Zn-protoporphyrin in experimental and perhaps clinical conditions in which hyperbilirubinaemia occurs.
非人类灵长类动物被用作人类新生儿高胆红素血症及其化学治疗抑制的模型。在新生恒河猴（猕猴）和食蟹猴（食蟹猕猴）的肝脏和脾脏中检测到高水平的血红素加氧酶活性。当给1日龄的新生动物单次皮下注射锌原卟啉（40 μmol/kg）时，血清胆红素水平在24小时内降至接近正常成年水平，并在整个产后时期（12天）保持被抑制状态。这种治疗抑制了肝脏和脾脏中血红素加氧酶和胆绿素还原酶的活性，而不影响大脑中的活性。锌原卟啉治疗并未改变大脑胆绿素还原酶的活性或增加大脑胆红素水平。通过测量金属卟啉复合物的胆汁和尿液排泄以及其在血细胞和组织中的摄取和沉积来研究锌原卟啉的生物学处置。金属卟啉的胆汁排泄极少（28小时内为0.12%），未检测到锌原卟啉尿液排泄的证据。然而，在实验期间（11天）红细胞中金属卟啉的浓度增加到这样的程度，即46%的给药化合物被细胞摄取。似乎锌原卟啉持续抑制血红素加氧酶活性和胆红素产生的分子基础涉及在胎儿红细胞降解的正常过程中金属卟啉的释放。就细胞色素P-450和b5的微粒体含量以及苯胺羟化酶而言，锌原卟啉改变血红素依赖性过程的生物活性范围在本质上似乎有限。此外，肝脏中谷胱甘肽的浓度未改变。这些发现表明锌原卟啉在发生高胆红素血症的实验条件以及可能的临床条件下具有潜在的用途。
