Effects of zinc deuteroporphyrin bis glycol on newborn mice after heme loading.
Effects of zinc deuteroporphyrin bis glycol on newborn mice after heme loading.
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DOI：
10.1203/pdr.0b013e31822e1675
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发表时间：
2011-11
影响因子：
3.6
通讯作者：
Stevenson DK
中科院分区：
文献类型：
--
作者：
He CX;Campbell CM;Zhao H;Kalish FS;Schulz S;Vreman HJ;Wong RJ;Stevenson DK
患有溶血性疾病的婴儿经常会出现高胆红素血症，但标准的光疗只能在胆红素产生后才能清除胆红素。一个更好的策略可能是直接抑制血红素加氧酶(HO)，这是产生胆红素的限速酶。金属卟啉(MPS)是一类血红素类似物，在体外和体内竞争性抑制HO活性，并在体内抑制血浆胆红素水平。一种很有前景的MP，次卟啉二甘醇锌(ZnBG)，在相对较低的剂量下可以被口服吸收并有效地抑制HO活性。我们测定了体内口服锌BG对HO活性抑制50%所需的I50(剂量)，然后评价了锌BG对血红素负载后新生小鼠体内胆红素生成、HO活性、HO蛋白水平和HO-1基因表达的影响。锌BG的I50为4.0Mol/kg体重(BW)。在15μ摩尔/kg体重剂量下，锌BG可降低体内胆红素的生成，抑制血红素诱导的肝HO活性和脾HO活性，瞬时诱导肝和脾HO-1基因转录，并诱导肝和脾HO-1蛋白水平。结论：锌BG可能是治疗溶血性疾病所致新生儿重症高胆红素血症的一种有吸引力的化合物。
Infants with hemolytic diseases frequently develop hyperbilirubinemia, but standard phototherapy only eliminates bilirubin after its production. A better strategy might be to directly inhibit heme oxygenase (HO), the rate-limiting enzyme in bilirubin production. Metalloporphyrins (Mps) are heme analogs that competitively inhibit HO activity in vitro and in vivo and suppress plasma bilirubin levels in vivo. A promising Mp, zinc deuteroporphyrin bis glycol (ZnBG), is orally absorbed and effectively inhibits HO activity at relatively low doses. We determined the I50 (the dose needed to inhibit HO activity by 50%) of orally administered ZnBG in vivo and then evaluated ZnBG’s effects on in vivo bilirubin production, HO activity, HO protein levels, and HO-1 gene expression in newborn mice following heme-loading, a model analogous to a hemolytic infant. The I50 of ZnBG was found to be 4.0 μmol/kg body weight (BW). At a dose of 15-μmol/kg BW, ZnBG reduced in vivo bilirubin production, inhibited heme-induced liver HO activity and spleen HO activity to and below baseline, respectively, transiently induced liver and spleen HO-1 gene transcription, and induced liver and spleen HO-1 protein levels. We conclude that ZnBG may be an attractive compound for treating severe neonatal hyperbilirubinemia caused by hemolytic disease.