Developmental hyperbilirubinemia and CNS toxicity in mice humanized with the UDP glucuronosyltransferase 1 (UGT1) locus
Developmental hyperbilirubinemia and CNS toxicity in mice humanized with the UDP glucuronosyltransferase 1 (UGT1) locus
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DOI：
10.1073/pnas.0913290107
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发表时间：
2010-03-16
影响因子：
11.1
通讯作者：
Tukey, Robert H.
中科院分区：
文献类型：
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作者：
Fujiwara, Ryoichi;Nguyen, Nghia;Tukey, Robert H.
新生儿高水平的未结合胆红素（UCB）与肝脏UDP糖醛基转移酶（UGT） 1A1活性降低有关，可导致中枢神经系统毒性、脑损伤甚至死亡。对于那些导致UCB在脑组织中积累的事件知之甚少，因此，我们试图在小鼠中复制这种情况。人类UGT1基因座编码包括UGT1A1在内的所有9-UGT1A基因，在UGT1（-/-）小鼠中表达。由于成人黄疸最常见的临床症状是吉尔伯特综合征，其特征是UGT1A1启动子的等位基因多态性，因此在表达吉尔伯特UGT1A1*28等位基因[Tg(UGT1(A1*28)) UGT1（-/-）小鼠]或正常UGT1A1*1等位基因[Tg(UGT1(A1* 1)) UGT1（-/-）小鼠]的人源化UGT1小鼠中监测高胆红素血症。成年Tg(UGT1(A1*28)) UGT1（-/-）小鼠与Tg(UGT1(A1*1)) UGT1（-/-）小鼠相比，总胆红素（TB）表达水平升高，证实与UGT1A1*28等位基因相关的启动子多态性有助于小鼠高胆红素血症。然而，结核在新生儿发育期间积累到接近毒性水平，这一发现与Gilbert's UGT1A1*28启动子多态性无关。虽然血清结核水平最终恢复到成年水平，但新生小鼠的结核清除与肝脏UGT1A1表达无关。在大约10%的人源化UGT1小鼠中，结核病水平的峰值在癫痫发作后达到顶峰，随后死亡。脑组织中的UCB沉积和随后的癫痫发作与发育里程碑有关，可以通过增强新生小鼠UGT1A1基因的调节来预防。
High levels of unconjugated bilirubin (UCB) in newborn children is associated with a reduction in hepatic UDP glucuronosyltransferase (UGT) 1A1 activity that can lead to CNS toxicity, brain damage, and even death. Little is known regarding those events that lead to UCB accumulation in brain tissue, and therefore, we sought to duplicate this condition in mice. The human UGT1 locus, encoding all 9-UGT1A genes including UGT1A1, was expressed in Ugt1(-/-) mice. Because the most common clinical condition associated with jaundice in adults is Gilbert's syndrome, which is characterized by an allelic polymorphism in the UGT1A1 promoter, hyperbilirubinemia was monitored in humanized UGT1 mice that expressed either the Gilbert's UGT1A1*28 allele [Tg(UGT1(A1*28))Ugt1(-/-) mice] or the normal UGT1A1*1 allele [Tg (UGT1(A1*1))Ugt1(-/-) mice]. Adult Tg(UGT1(A1*28))Ugt1(-/-) mice expressed elevated levels of total bilirubin (TB) compared with Tg(UGT1(A1*1)) Ugt1(-/-) mice, confirming that the promoter polymorphism associated with the UGT1A1*28 allele contributes to hyperbilirubinemia in mice. However, TB accumulated to near toxic levels during neonatal development, a finding that is independent of the Gilbert's UGT1A1*28 promoter polymorphism. Whereas serum TB levels eventually returned to adult levels, TB clearance in neonatal mice was not associated with hepatic UGT1A1 expression. In similar to 10% of the humanized UGT1 mice, peak TB levels culminated in seizures followed by death. UCB deposition in brain tissue and the ensuing seizures were associated with developmental milestones and can be prevented by enhancing regulation of the UGT1A1 gene in neonatal mice.