TY - JOUR
T1 - Bilirubin UDP-glucuronosyltransferase 1 is the only relevant bilirubin glucuronidating isoform in man
AU - Bosma, Piter J.
AU - Seppen, Jurgen
AU - Goldhoorn, Bart
AU - Bakker, Conny
AU - Oude Elferink, Ronald P.J.
AU - Chowdhury, Jayanta Roy
AU - Chowdhury, Namita Roy
AU - Jansen, Peter L.M.
N1 - Copyright: Copyright 2014 Elsevier B.V., All rights reserved.
PY - 1994/7/8
Y1 - 1994/7/8
N2 - Crigler-Najjar syndrome type I (CN-I) is caused by an inherited absence of UDP-glucuronosyltransferase activity toward bilirubin (B-UGT), resulting in severe nonhemolytic 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.
AB - Crigler-Najjar syndrome type I (CN-I) is caused by an inherited absence of UDP-glucuronosyltransferase activity toward bilirubin (B-UGT), resulting in severe nonhemolytic 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.
UR - http://www.scopus.com/inward/record.url?scp=0028276410&partnerID=8YFLogxK
M3 - Article
C2 - 8027054
SN - 0021-9258
VL - 269
SP - 17960
EP - 17964
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 27
ER -