UGT1A Gene Structure

UDP-glucuronosyltransferases (UGTs) catalyze the transfer of a glucuronoic acid from uridine diphosphoglucuronic acid to a variety of endogenous and exogenous compounds. The major function of these enzymes is to change hydrophobic compounds into soluble derivatives and thereby facilitate their detoxification and excretion into the bile or urine. Among four subfamilies of UGTs identified in humans (i.e., UGT1, UGT2, UGT3, and UGT8) (20),

UGT1A isozymes, such as 1A1, 1A7, 1A9, and 1A10, are known to glucuronidate SN-38 (3,4,5,6,13). The human UGT1A gene complex spans approximately 200kb on chromosome 2q37, and consists of nine active (1AS, 1A10, 1A9, 1A7, 1A6, 1A5, 1A4, 1A3, and 1A1) and four inactive (1A12P, 1A11P, 1A13P, and 1A2P) exon 1 segments and common exons 2-5 (Block C) (Fig. 2). Each UGT1A gene transcript is formed by splicing one of the first exons with the common exons 2-5 (Block C).

The first exon of each UGT1A isoform encodes the N-terminal domain of the enzyme, which determines the substrate-binding specificity. The common exons 2-5 (Block C) encode the C-terminal domain that is essential for the binding of UDP-glucuronoic acid (21). UGT1A1, 1A3, 1A4, 1A6, and 1A9 are expressed in the liver as well as in extra-hepatic tissues, including the gastrointestinal tract, while UGT1A7, 1A8, and 1A10 are detected in the extrahepatic tissues (22,23,24).

The 5'-flanking region of each first exon is presumed to regulate expression of each UGT1A isoform, whereas the mechanisms for its basal expression and induction by endogenous or exogenous compounds have not yet been fully elucidated. There are large interindividual differences in UGT1A content and activities in various tissues, and the UGT1A genetic polymorphisms in the promoter or coding regions have been implicated as one of the sources of these variations. The following sections describe the genetic

Ugt1a Gene
Fig. 2. Structure of the UGT1A gene complex and the major UGT1A1, 1A7, and 1A9 polymorphisms.

polymorphisms and haplotypes of UGT1A1, 1A7, 1A9 and 1A10 that are responsible for glucuronidation of SN-38 (4,5,6).

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