Glucuronyltransferase

The enterocyte expresses many of the metabolic enzymes that are expressed in the liver. These include UDP-glucuronyltransferases, sulfotransferases, esterases and cytochromes P450. 

UDP-glucuronyltransferases catalyze the addition of glucuronic acid onto phenol, hydroxyl and carboxylic acid functions of molecules. They are expressed in many tissues of the body, including the liver and intestine [2-5], Microsomes from human intestines have been shown to metabolize UDP-glucuronyltransferase substrates including p-nitrophenol [6], 1-naphthol, morphine, and ethinylestradiol [4]. The relative rates of metabolism of these substrates in liver and intestinal microsomes are shown in Table 13.1. 

Overall, the human intestine is capable of metabolizing UDP-glucuronyltransferase substrates, although the rates of metabolism are between 5- and 10-fold lower than those observed in human liver microsomes. However, the presence of a metabolic capacity towards UDP-glucuronyltransferase substrates at the level of the enterocyte can exert a significant gut wall first-pass extraction on oral administration. 

From the above, it is clear that the gut wall represents more than just a physical barrier to oral drug absorption. In addition to the requirement to permeate the membrane of the enterocyte, the drug must avoid metabolism by the enzymes present in the gut wall cell as well as counter-absorptive efflux by transport proteins in the gut wall cell membrane. Metabolic enzymes expressed by the enterocyte include the cytochrome P450, glucuronyltransferases, sulfotransferases and esterases. The levels of expression of these enzymes in the small intestine can approach that of the liver. The most well-studied efflux transporter expressed by the enterocyte is P-gp. 

Cats and pigs have low activities of phenol glucuronyltransferase, and metabolize phenol to phenyl sulfate nearly exclusively (Capel et al. 1972 French et al. 1974 Miller et al. 1976). Because humans have a greater capacity to glucuronidate phenol, cats and pigs would not be good models for the metabolism of phenol by humans. 

Mulder GJ, Scholtens E. 1977. Phenol sulphotransferase and uridine diphosphate glucuronyltransferase from rat liver in vivo and in vitro. Biochem J 165 553-559. 

Glucuronidation Alcohols/phenols Carboxylic acids Glucuronyltransferases a- or //-glucuronides... 

Raijmakers, M.T., Jansen, P.L., Steegers, E.A., et al. (2000) Association of human liver bilirubin UDP-glucuronyltransferase activity with a polymorphism in the promoter region of the UGTIAI gene. J. Hepatol. 33, 348-351. 

Glucuronidation Alcohols or phenols Carboxylic acids Amines Thiols Glucuronyltransferases (UDP-glucuronic acid) a- or 8-Glucuronides... 

Two other structurally characterized transferases have the same or almost the same mode of Mn + coordination as Mn + in Bacillus subtilis glycosyltransferase SpsA described above. A-acetylglucosaminyltransferase I which serves as the gateway from oligomannose to hybrid and complex A-glycans and plays a critical role in mammalian development, has the same active site structure except the Mg + ion and the glycerol are not present. /3 1,3-Glucuronyltransferase I... 

The present review covers a description of methodology and properties of UDP-glucuronyltransferase and of related UDP-glycosyltransferase activities (assayed with bilirubin as the acceptor substrate) and attempts to delineate applications to human disease. Studies with other hydro-phobic acceptor substances will be discussed as far as relevant to the subject matter. 

Conjugation with glucuronyl residues is of great importance for the metabolic fate of bilirubin (S3), steroids (L5, M2, R8), catecholamines (W17) and other hydrophobic compounds (D8, D9). Neonatal accumulation of bilirubin in man and rats may trigger maturation of UDP-glucuronyltransferase (Bl, B2, T6). Delayed maturation of the enzyme, or its partial or total deficiency, are critical factors in the development of kernicterus (P6). Compared to other species partial deficiency of the... 

Studies of UDP-glucuronyltransferase with bilirubin as the acceptor substrate are technically difficult. This is indicated by frequent modification of the initial assay systems (A8, G9, L4, S4) and by the wide range of reported enzyme activities (Table 1). Possible causes of these discrepancies, which are manyfold, will be discussed in some detail below. The conclusions drawn should be helpful in the design of assays of conjugate formation of bilirubin and of the synthesis of mono- and diconjugates. 

No data are available regarding effects of competing enzymes on the activities of transferases other than glucuronyltransferase. For assays of native transglucuronylation rates, it may be useful to run parallel incubations with UDP-N-acetylglucosamine-fortified (SIO) and unfortified preparations, particularly when species are compared. 

With albumin-solubilized bilirubin, pH optima of microsomal bilirubin UDP-glucuronyltransferase were 7.4-8.0 for rat (H2, HIO, SIO) and 7.4 for guinea pig (M13) and rabbit (T8). Above pH 8 the enzyme activity decreased abruptly (HIO). In absence of carrier protein, optima were at pH 8 and 8.2 with preparations from liver of guinea pig (P3) and rat (W12), respectively. The activity-pH curve with optimum at pH 8.2 (W12) showed pronounced skewing, with a steady and rather rapid increase of enzyme activity from pH 7.4 to 8.2. One may wonder whether such measurements were influenced by the rapid increase of solubility of the acceptor substrate occurring over the same pH range (B25). 

The effects of Mg-+ on UDP-glucuronyltransferase depend on preparations and substrates (D9, L14). Bilirubin UDP-glucuronyltransferase in untreated (F17, W12) and detergent-activated microsomal preparations from rat liver (HIO, Y2) and in purified fractions (A2, H2), is stimulated by Mg +. Employing purified enzyme (probably still linked to a piece of... 

With bilirubin UDP-glucuronyltransferase from rat liver, Mn-+ was more (HIO), and Ca + less, stimulatory than Mg + (A2, F17, HIO). The behavior was similar when either UDP-glucose or UDP-xylose was used as the glycosyl donor (F3). Enzyme activities were also stimulated by Fe and Co (F3, HIO) Pb + activated glucuronyl transfer but was inhibitory with the other UDP-sugars. The effects of Mg +, Mn +, and Co are in accordance with work of Lucier et al. (L14) on the catalysis of glucuronyl transfer to p-nitrophenol and 1-naphthol by Triton X-100-activated and untreated microsomal material from rat liver. 

With the exception of a recent bisubstrate kinetic analysis of bilirubin UDP-glucuronyltransferase (P5), saturation with either one of the substrates was investigated at some rather arbitrarily fixed concentration of the other substrate. The results, therefore, have to be interpreted with caution. 

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