Drummond G S, Galbraith R A, Sardana M K, Kappas A
Arch Biochem Biophys. 1987 May 15;255(1):64-74. doi: 10.1016/0003-9861(87)90294-3.
Sn (tin)-mesoporphyrin (Sn-protoporphyrin in which the vinyl groups at C2 and C4 have been reduced to ethyl groups) when incubated with rat splenic microsomal heme oxygenase proved to be a potent competitive inhibitor of enzyme activity in vitro, with a Ki of 0.014 microM. Sn-mesoporphyrin (1 mumol/kg body wt) also inhibited hepatic, renal, and splenic heme oxygenase activity in vivo in adult animals for extended periods of time. Sn-mesoporphyrin (1 mumol/kg body wt) prevented the transient increase in serum bilirubin 24 h after birth in the rat neonate and substantially reduced the levels of serum bilirubin in ALA (delta-aminolevulinic acid) induced hyperbilirubinemia in the 7-day-old suckling neonate. Tissue heme oxygenase activity was decreased in both animal models of hyperbilirubinemia. Sn-mesoporphyrin administration led to a prolonged increase in the heme saturation of hepatic tryptophan pyrrolase indicating an increase in the "heme pool" related to tryptophan pyrrolase and the compound also suppressed chemically induced hepatic porphyria. The administration of Sn-mesoporphyrin to bile duct-cannulated rats was followed by a prompt and sustained decrease in bilirubin output in bile. In addition the excretion of heme in bile was enhanced in these animals. These studies indicate that Sn-mesoporphyrin, like Sn-protoporphyrin, decreases serum bilirubin by inhibiting the production of bilirubin in vivo and its mode of action is through a sustained competitive inhibition of heme oxygenase. However, when a direct comparison of Sn-protoporphyrin and Sn-mesoporphyrin was made, these studies clearly established that the reduction of the C2 and C4 vinyl groups of the porphyrin macrocycle to ethyl groups increases the effectiveness of the Sn-mesoporphyrin derivative 10-fold or more as compared with Sn-protoporphyrin in inhibiting heme catabolism in the animal model systems examined. Thus alterations in the side chain substituents as well as of the central metal atom can influence in a significant manner the potency of the resultant synthetic heme analog as an agent capable of inhibiting heme degradation in vivo.
锡（Sn）-中卟啉（C2和C4位的乙烯基还原为乙基后的Sn-原卟啉）与大鼠脾脏微粒体血红素加氧酶一起温育时，在体外被证明是该酶活性的一种强效竞争性抑制剂，其抑制常数（Ki）为0.014微摩尔。锡-中卟啉（1微摩尔/千克体重）在成年动物体内也能长时间抑制肝脏、肾脏和脾脏的血红素加氧酶活性。锡-中卟啉（1微摩尔/千克体重）可防止新生大鼠出生后24小时血清胆红素的短暂升高，并能显著降低7日龄哺乳新生大鼠因δ-氨基乙酰丙酸（ALA）诱导的高胆红素血症中的血清胆红素水平。在这两种高胆红素血症动物模型中，组织血红素加氧酶活性均降低。给予锡-中卟啉会导致肝脏色氨酸吡咯酶的血红素饱和度长时间升高，这表明与色氨酸吡咯酶相关的“血红素池”增加，并且该化合物还能抑制化学诱导的肝卟啉症。给胆管插管的大鼠注射锡-中卟啉后，胆汁中的胆红素排出量迅速且持续减少。此外，这些动物胆汁中的血红素排泄增加。这些研究表明，锡-中卟啉与锡-原卟啉一样，通过抑制体内胆红素的生成来降低血清胆红素，其作用方式是通过持续竞争性抑制血红素加氧酶。然而，当对锡-原卟啉和锡-中卟啉进行直接比较时，这些研究清楚地表明，在受试动物模型系统中，卟啉大环C2和C4位的乙烯基还原为乙基后，锡-中卟啉衍生物抑制血红素分解代谢的效力比锡-原卟啉提高了10倍或更多。因此，侧链取代基以及中心金属原子的改变能够显著影响所得合成血红素类似物作为体内抑制血红素降解药物的效力。
