UDP-Glucuronosyltransferases

Abstract

Glucuronidation represents a major pathway which enhances the elimination of many lipophilic xenobiotics and endobiotics to more water-soluble compounds. The UDP-glucuronosyltransferase (UGT) family catalyzes the glucuronidation of the glycosyl group of a nucleotide sugar to an acceptor compound (aglycone) at a nucleophilic functional group of oxygen (eg, hydroxyl or carboxylic acid groups), nitrogen (eg, amines), sulfur (eg, thiols), and carbon, with the formation of a beta-D-glucuronide product. At this time, over 35 different UGT gene products have been described from several different species. UGTs have been divided into two distinct subfamilies based on sequence identities, UGT1 and UGT2. The UGT1 gene subfamily consists of a number of UGTs that result from alternate splicing of multiple first exons and share common exons 2-5. The substrate specificities of the various isoforms have been examined in cultured cell experiments, and include bilirubin, amines, and planar and bulky phenol. The UGT2 gene family is different in that the UGT2 mRNAs are transcribed from individual genes. The UGT2 subfamily consists of numerous enzymes which catalyze the glucuronidation of a diverse chemical base including steroids, bile acids, and opioids. Until recently, the liver has been the major focus for studying the metabolism of xenobiotics and endobiotics. Several groups have identified extrahepatic tissues that express UGT isoforms including the kidney, gastrointestinal tract and brain. This review discusses the two UGT gene families, substrate specificities, and the recent discoveries of UGTs in extrahepatic tissues.

Influence of chronic hepatic failure on disposition kinetics of valproate excretion through a phase II reaction in rats treated with carbon tetrachloride

“…It is reported that the amounts of UGT mRNA isoforms in liver of rats are variable [15], but the enzyme activity of UGTs is predominantly dependent on the expression of UGT1A1, 1A6 and 1A7 mRNAs [16]. In this study, the mRNA levels of UGT1A6 and 1A7 were significantly increased in the liver of rats with chronic hepatic failure, whereas that of UGT1A1 was significantly decreased (Fig.…”

Glucuronidation and sulfonation, in vitro, of the major endocrine-active metabolites of methoxychlor in the channel catfish, Ictalurus punctatus, and induction following treatment with 3-methylcholanthrene

“…K m values in this range are not unusual for xenobiotic aglycones (King et al, 2000), suggesting a low affinity of these substrates for glucuronidation, however these K m values are considerably higher than the 1 μM K m value for 3-hydroxy-benzo(a)pyrene found with channel catfish intestinal microsomes (James et al, 2001). Comparison of the V max values for OH-MXC and HPTE shows that V max is higher for OH-MXC, and suggests that OH-MXC will be more readily glucuronidated than HPTE in the catfish liver.…”

Pharmacogenomics of human UDP-glucuronosyltransferase enzymes

“…UGTs are also expressed in a wide variety of tissues, including brain, prostate, uterus, breast, placenta and kidney, to name only a few. 11,[76][77][78][79][80] The molecular genetics of human UGTs is now more clearly understood, with evidence for the existence of distinct subfamilies, which comprise more than 26 genes or cDNAs (Figure 2). Eighteen of them correspond to functional proteins and are encoded by two gene families, UGT1 and UGT2 that are, based on their sequence similarities, further divided into three subfamilies: UGT1A, UGT2A and UGT2B (for detailed information see Mackenzie et al 81 ).…”

“…The UGT2B7 protein is also found in the brain, kidney, pancreas, mammary gland, lung and gastrointestinal tract, and several additional tissues. 80,134,138,[144][145][146] A cytosine to thymine polymorphism at base pair 802, leading to a histidine (H) 268 to tyrosine (Y) amino-acid substitution (UGT2B7*2), has been identified. 147,148 Data from large genotyping studies suggest that approximately one-third of the Caucasian population expresses the variant UGT2B7*2/*2 genotype (Table 5).…”