Regulation of the UGT1A1 bilirubin‐conjugating pathway: Role of a new splicing event at the UGT1A locus

摘要: UDP-glucuronosyltransferase 1A1 (UGT1A1) is involved in a wide range of biological and pharmacological processes because its critical role the conjugation diverse array endogenous exogenous compounds. We now describe new UGT1A1 isoform, referred to as isoform 2 (UGT1A1_i2), encoded by 1495-bp complementary DNA isolated from human liver generated an alternative splicing event involving additional exon found at 3′ end UGT1A locus. The N-terminal portion 45-kd UGT1A1_i2 protein identical (55 kd, UGT1A1_i1); however, contains unique 10-residue sequence instead 99–amino acid C-terminal domain UGT1A1_i1. RT-PCR Western blot analyses with specific antibody against indicate that differentially expressed liver, kidney, colon, small intestine levels reach or exceed, for some tissues, those 1. blots different cell fractions immunofluorescence experiments UGT1A1_i1 colocalize microsomes. Functional enzymatic data UGT1A1_i2, which lacks transferase activity when stably alone HEK293 cells, acts negative modulator UGT1A1_i1, decreasing up 78%. Coimmunoprecipitation suggests this repression may occur via direct protein–protein interactions. Conclusion: Our results newly discovered mechanism locus amplifies structural diversity UGT proteins describes identification posttranscriptional regulatory glucuronidation pathway. (HEPATOLOGY 2007;45:128–138.)