UDPglucuronosyltransferases EC 24117

Conjugation with glucuronic acid is the most abundant phase-II reaction (see 5.06 Principles of Drug Metabolism 2: Hydrolysis and Conjugation Reactions). UDP-glucuronosyltransferases (UGTs)52 catalyze the formation of beta-D-glucuronides from a large variety of xenobiotics by their reaction with UDP-glucuronic acid (UDPGA). Hydroxyl-, thiol-, amino-, hydroxylamino- and carboxyl-substituents serve as the anchor to which glucuronic acid can be conjugated (also C-glucuronides can be formed if the hydrogen of the respective C-H bond is sufficiently mobile such as a carbon atom between two carbonyl functions). The xenobiotic substituents engaged in the glucuronic acid conjugation are nucleophilic. Accordingly, the majority of the UGT substrates are not genotoxic. The anchor groups listed above are often determinants or co-determinants of the biological activity of drugs and toxins, since they are frequently involved in the interaction with receptors or enzymes. Therefore, conjugation of these frequently terminates therapeutic or also toxic activity. Additionally, in most cases, glucuronic acid conjugation substantially increases the hydrophilicity of a drug enhancing its excretion. Hence, UGTs are predominantly detoxifying enzymes.1

In a few cases, however, UGTs enhance the toxicity of their substrates. This is the case with some nonsteroidal anti-inflammatory drugs (NSAIDs). The resulting ester glucuronides can undergo acyl migration, i.e., the intramolecular transesterification from the C1 hydroxy group of the glucuronic acid to the C2 hydroxy group and further to the C3 and C4 hydroxy groups. This can lead to the formation of a free aldehyde group at C1, which can react with primary amino groups in proteins generating Schiff's bases. Amadori rearrangement can then lead to a stable protein adduct, which may give rise to allergic reactions, a well-known drug toxicity of some NSAIDs. Glucuronic acid conjugation can also result in enhanced genotoxicity. Aromatic amines, including important human carcinogens, are metabolized by CYPs (preferentially CYP1A2) to aromatic hydroxylamines. Glucuronidation of these leads to the formation of a (moderately good) leaving group, which after being cleaved off leaves behind a strongly electrophilic and genotoxic aryl nitrenium ion. Mildly acidic conditions, which are usually present in the urine, but not neutral pH, suffice to produce this situation. The hydroxylamines are converted into glucuronides as transport forms, which survive their journey in the blood from the liver where they are produced to the bladder where they dissociate and lead to bladder cancer (alternative conjugation reactions, sulfation and acetylation, of aromatic hydroxylamines form better leaving groups, which already dissociate at neutral pH).1,53

The families and subfamilies of UGTs52 are described elsewhere in this book (see 5.06 Principles of Drug Metabolism 2: Hydrolysis and Conjugation Reactions). The most important family toxicologically is UGT1. A single gene codes for at least 10 different proteins of this family. Differential splicing results in mRNAs that differ in the sequence of their first exon and are identical in the sequences of exons 2-5. The N-terminal portions of the resulting proteins, which correspond to the variable exon 1, contain the substrate binding sites. Therefore, the corresponding UGTs differ in their substrate specificities. These range from the endogenous bilirubin to pharmacologically active drugs such as morphine, to carcinogen precursors, such as benzo[a]pyrene-7,8-dihydrodiol. Therefore, a defect in this gene can have dramatic consequences. Heritable human diseases that have been attributed to such defects are the Crigler-Najjar syndrome and the Gilbert syndrome. The hyperbilirubinemia that results from the reduced or lost capacity to detoxify bilirubin can lead to an early death (Crigler-Najjar type 1). An experimental model for this disease is the Gunn rat. Owing to a mutation in exon 2 it lacks all UGT1 proteins. Rats are less sensitive than humans to the toxic action of bilirubin. Gunn rats can survive the lack of these UGTs, which makes them useful as a tool for studying the toxicological consequences of this defect.1

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