Drummond G S, Kappas A
J Clin Invest. 1984 Jul;74(1):142-9. doi: 10.1172/JCI111394.
A model of experimental postnatal hyperbilirubinemia in the rat has been developed utilizing the heme precursor delta-aminolevulinic acid (ALA) to produce jaundice during a selective time period after birth. This time period is defined as that between 7 d postnatally, when the initial postpartum alterations of serum bilirubin and heme metabolism in the neonate have subsided, and 21 d, when the hepatic conjugation mechanism for the bile pigment appears fully developed. Administration of ALA in this time period led to a rapid, consistent, and significant dose-dependent increase in serum bilirubin levels in the newborn animals. Heme administration produced a qualitatively similar but enhanced effect. Both compounds, in addition, induced a dose-dependent increase in hepatic heme oxygenase activity concomitant with the increase in serum bilirubin levels. Neither compound increased serum bilirubin levels significantly when administered at or after 21 d postnatally. Administration of the synthetic metalloporphyrin, Sn-protoporphyrin, to ALA-treated neonates resulted in a dose-dependent decrease in serum bilirubin levels and hepatic heme oxygenase activity. Mn- and Zn-protoporphyrin in comparable doses did not significantly inhibit ALA-induced hyperbilirubinemia. Sn-protoporphyrin also inhibited the hyperbilirubinemia produced by heme in the suckling animals. ALA administration to newborn rats during the specific postnatal period described provides a simple and convenient model of experimental jaundice in the developing neonate which permits an examination of the potential ability of synthetic metalloporphyrins or other compounds to suppress induced hyperbilirubinemia in the newborn animal. The ability to induce a consistent and significant degree of jaundice in the postnatal rat by the method described may also be useful for other types of studies concerned with the biological disposition and effects of endogenously formed bilirubin in the neonate. The results of this study confirm in another model system the potent ability of Sn-protoporphyrin to suppress jaundice in the neonate, and suggest that suppression of heme oxidation by synthetic heme analogues may represent a useful therapeutic approach to the problem of severe hyperbilirubinemia in human premature newborn.
利用血红素前体δ-氨基乙酰丙酸（ALA），已建立了一种大鼠实验性产后高胆红素血症模型，以在出生后的特定时间段内产生黄疸。该时间段定义为出生后7天至21天之间，7天时新生儿血清胆红素和血红素代谢的初始产后变化已消退，21天时胆汁色素的肝脏结合机制似乎已完全发育。在此时间段内给予ALA导致新生动物血清胆红素水平迅速、持续且显著的剂量依赖性升高。给予血红素产生了定性相似但增强的效果。此外，两种化合物均诱导肝脏血红素加氧酶活性的剂量依赖性增加，同时血清胆红素水平升高。当在出生后21天或之后给予时，两种化合物均未显著增加血清胆红素水平。向ALA处理的新生儿给予合成金属卟啉锡原卟啉，导致血清胆红素水平和肝脏血红素加氧酶活性呈剂量依赖性降低。同等剂量的锰原卟啉和锌原卟啉未显著抑制ALA诱导的高胆红素血症。锡原卟啉也抑制了哺乳动物中血红素产生的高胆红素血症。在所述特定产后时期向新生大鼠给予ALA提供了一种发育中新生儿实验性黄疸的简单方便模型，该模型允许检查合成金属卟啉或其他化合物抑制新生动物中诱导的高胆红素血症的潜在能力。通过所述方法在产后大鼠中诱导一致且显著程度黄疸的能力也可能对其他类型的研究有用，这些研究涉及新生儿内源性形成的胆红素的生物学处置和作用。本研究结果在另一个模型系统中证实了锡原卟啉抑制新生儿黄疸的强大能力，并表明合成血红素类似物对血红素氧化的抑制可能代表一种治疗人类早产新生儿严重高胆红素血症问题的有用治疗方法。
