Bilirubin UDP-glucuronosyltransferase 1 is the only relevant bilirubin glucuronidating isoform in man

Piter J. Bosma, Jurgen Seppen, Bart Goldhoorn, Conny Bakker, Ronald P J Oude Elferink, Jayanta Roy-Chowdhury, Namita Roy Chowdhury, Peter L M Jansen

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)17960-17964
Number of pages5
JournalJournal of Biological Chemistry
Volume269
Issue number27
StatePublished - Jul 8 1994

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bilirubin glucuronoside glucuronosyltransferase
Bilirubin
Protein Isoforms
Exons
COS Cells
Mutation
Crigler-Najjar Syndrome
Complementary DNA
Glucuronosyltransferase
Hyperbilirubinemia

ASJC Scopus subject areas

  • Biochemistry

Cite this

Bosma, P. J., Seppen, J., Goldhoorn, B., Bakker, C., Oude Elferink, R. P. J., Roy-Chowdhury, J., ... Jansen, P. L. M. (1994). Bilirubin UDP-glucuronosyltransferase 1 is the only relevant bilirubin glucuronidating isoform in man. Journal of Biological Chemistry, 269(27), 17960-17964.

Bilirubin UDP-glucuronosyltransferase 1 is the only relevant bilirubin glucuronidating isoform in man. / Bosma, Piter J.; Seppen, Jurgen; Goldhoorn, Bart; Bakker, Conny; Oude Elferink, Ronald P J; Roy-Chowdhury, Jayanta; Chowdhury, Namita Roy; Jansen, Peter L M.

In: Journal of Biological Chemistry, Vol. 269, No. 27, 08.07.1994, p. 17960-17964.

Research output: Contribution to journalArticle

Bosma, PJ, Seppen, J, Goldhoorn, B, Bakker, C, Oude Elferink, RPJ, Roy-Chowdhury, J, Chowdhury, NR & Jansen, PLM 1994, 'Bilirubin UDP-glucuronosyltransferase 1 is the only relevant bilirubin glucuronidating isoform in man', Journal of Biological Chemistry, vol. 269, no. 27, pp. 17960-17964.
Bosma PJ, Seppen J, Goldhoorn B, Bakker C, Oude Elferink RPJ, Roy-Chowdhury J et al. Bilirubin UDP-glucuronosyltransferase 1 is the only relevant bilirubin glucuronidating isoform in man. Journal of Biological Chemistry. 1994 Jul 8;269(27):17960-17964.
Bosma, Piter J. ; Seppen, Jurgen ; Goldhoorn, Bart ; Bakker, Conny ; Oude Elferink, Ronald P J ; Roy-Chowdhury, Jayanta ; Chowdhury, Namita Roy ; Jansen, Peter L M. / Bilirubin UDP-glucuronosyltransferase 1 is the only relevant bilirubin glucuronidating isoform in man. In: Journal of Biological Chemistry. 1994 ; Vol. 269, No. 27. pp. 17960-17964.
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abstract = "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.",
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