Bilirubin UDP-glucuronosyltransferase 1 is the only relevant bilirubin glucuronidating isoform in man.
Bilirubin UDP-glucuronosyltransferase 1 is the only relevant bilirubin glucuronidating isoform in man.
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发表时间：
1994-07
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通讯作者：
P. Bosma;J. Seppen;B. Goldhoorn;C. Bakker;R. Elferink;J. Chowdhury;N. Chowdhury;N. Chowdhury;P. Jansen
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作者：
P. Bosma;J. Seppen;B. Goldhoorn;C. Bakker;R. Elferink;J. Chowdhury;N. Chowdhury;N. Chowdhury;P. Jansen
Crigler-Najjar综合征I型（CN-I）是由遗传性缺乏针对胆红素的UDP-葡萄糖醛酸基转移酶活性（B-UGT）引起的，导致严重的非溶血性未结合型高胆红素血症。基于cDNA在COS细胞中的表达，已报道人肝脏中的两种UGT同工型B-UGT 1和B-UGT 2催化胆红素葡萄糖醛酸化。这些异构体，这是来自一个单一的基因，ugt 1，具有相同的羧基末端结构域，这是由四个连续的外显子编码的两种异构体共享。在这些共同外显子中的任何一个关键病变都应该使两种B-UGT亚型重叠，引起CN-I。B-UGT同种型的氨基末端结构域是独特的，每个结构域由不同的5'外显子编码。如果两种B-UGT亚型均显著促进胆红素葡萄糖醛酸化，则这些独特5'外显子之一的突变应影响单一亚型，而其他亚型应提供残留B-UGT活性。然而，在两名CN-I患者中，我们发现仅在B-UGT 1的独特外显子中发生突变，其他外显子均正常。为了澄清这一明显的矛盾，我们在COS细胞中表达了每个B-UGT亚型的cDNA，并测定了特定的B-UGT活性。这些研究表明，只有B-UGT 1具有定量显著的催化活性。此外，我们发现在两名CN-I患者中观察到的B-UGT 1突变使B-UGT 1失活。总之，结果表明B-UGT 1是胆红素葡萄糖醛酸化中唯一的生理学相关亚型。
Crigler-Najjar syndrome type I (CN-I) is caused by an inherited absence of UDP-glucuronosyltransferase activity toward bilirubin (B-UGT), resulting in severe non-hemolytic unconjugated hyperbilirubinemia. Based on the expression of cDNAs in COS cells, two UGT isoforms in human liver, B-UGT1 and B-UGT2, have been reported to catalyze bilirubin glucuronidation. These isoforms, which are derived from a single gene, ugt1, have identical carboxyl-terminal domains that are encoded by four consecutive exons shared by both isoforms. A critical lesion in any of these common exons should inactivate both B-UGT isoforms, giving rise to CN-I. The amino-terminal domains of the B-UGT isoforms are unique, each being encoded by a different 5' exon. If both B-UGT isoforms contribute significantly to bilirubin glucuronidation, a mutation in one of these unique 5' exons should affect a single isoform, while the other isoforms should provide residual B-UGT activity. However, in two patients with CN-I, we found a mutation only in the unique exon of B-UGT1, the other exons being normal. To clarify this apparent paradox, we expressed the cDNA for each B-UGT isoform in COS cells and determined the specific B-UGT activity. These studies show that only B-UGT1 has quantitatively significant catalytic activity. Furthermore, we show that the mutation in B-UGT1 observed in each of the two CN-I patients inactivates B-UGT1. Together, the results indicate that B-UGT1 is the only physiologically relevant isoform in bilirubin glucuronidation.