UDP-glucuronosyl-transferases

2 ROLES OF PHASE II GENES AND POLYMORPHISMS 13.2.1 UDP-Glucuronosyl Transferases 

SXR Steroid end xenobiotics receptor (human] CAR Constitutive active (androstane) receptor other UGT substrates 

Crigler-Najjar Syndrome Mutations in the UGT1A1 gene 

Type I no UGT1A1 activity severe blood exchange, transfusion or Type II 10% of normal UGT1A1 activity UveMransplantatlon 

NucleotEde Allele Changes Protein Chances Type Exon Disease 

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Figure 32-14. Conjugation of bilirubin with glucuronic acid. The glucuronate donor, UDP-glucuronic acid, is formed from UDP-glucose as depicted. The UDP-glucuronosyl-transferase is also called bilirubin-UGT.

Polyphenols and flavanoids in rat liver microsomal fractions have been demonstrated to inhibit glucuronidation of estrone and estradiol in vitro (Zhu et al, 1998). In addition, flavonoids have also been found to induce phase I and II enzymes in rats including UDP-glucuronosyl transferase (Seiss et al, 1996). However, the effects of phytoestrogens have not been evaluated for either their inhibition or induction of glucuronosyl transferase activity. 

Hansen, K.T. and Stentoft, K. (1995) Characterization of benzazepine UDP-glucuronosyl-transferases in laboratory animals and man. Xenobiotica The Fate of Foreign Compounds in Biological Systems, 25,611-622. 

Capiello, M., Guiliani, L., Pacifici, G. M., Distribution of UDP-glucuronosyl transferase and its endogenous substrate uridine 5-diphosphoglucuronic acid in human tissues, Pur. J. Clin. Pharmacol. 1991, 41, 345-350. 

Bosma PJ, Chowdhury JR, Barker C et al. The genetic basis of the reduced expression of bilimbin UDP-glucuronosyl-transferase 1 in Gilbert s syndrome. 

Zhou, J., Zhang, J. and Xie, W. (2005) Xenobiotic nuclear receptor-mediated regulation of UDP-glucuronosyl-transferases. Current Drug Metabolism, 6, 289-298. 

Unconjugated bilirubin is taken into the hepatocytes by binding to membrane transport proteins and transported through the liver cells to the SER by proteins called ligandins. The SER is the location of a specific bilirubin-UDP-glucuronosyl transferase... 

Collier AC, Tingle MD, Keelan JA, Paxton JW, Mitchell MD (2000) A highly sensitive fluorescent microplate method for the determination of UDP-glucuronosyl transferase activity in tissues and placental cell lines. Drug Metab Dispos 28(10) 1184-1186... 

Beutler, E., Gelbart, T., and Demina, A. (1998) Racial variability in the UDP-glucuronosyl-transferase 1 (UGTIAI) promoter a balanced polymorphism for regulation of bilirubin metabolism Proc. Natl. Acad. Sci. U. S. A. 95, 8170-8174. 

Hyperbilirubinemia Most patients taking atazanavir experience asymptomatic elevations in indirect (unconjugated) bilirubin related to inhibition of UDP-glucuronosyl transferase (UGT). This hyperbilirubinemia is reversible upon discontinuation of atazanavir. 

Aono S, Yamada Y, Keino Het al. Identification of defect in the genes for bilirubin UDP-glucuronosyl-transferase in a patient with Crigler-Najjar syndrome type II. Biochem Biophys Res Commun 1993 197 1239-1244. 

The other primary Phase II metabolic pathway is glucuronidation, which involves the formation ofglucuronic acid conjugates of xenobiotics. This is catalyzed by a family of UDP-glucuronosyl transferases (UGTs) in the presence of uridine diphosphate... 

TCDD binds to the AhR and initiates a number of responses as well as induction of CYP1A1, including induction of UDP-glucuronosyl transferases, GSH transferases, and stimulation of apoptosis in thymocytes, resulting in thymic atrophy. 

Figure 7.9 The metabolism and metabolic activation of tamoxifen. Abbreviations SULT, sulfotransferase UGT, UDP-glucuronosyl transferase.

Tetrachloroethane causes central nervous system depression and is highly hepatotoxic in mice and dogs it produced embryotoxic effects and a low incidence of malformations in mice. A single oral dose (437 mg/kg bw) of 1,1,2,2-tetrachloroethane decreased the activity of some hepatic cytochrome P450-dependent monooxygenases and, to a smaller extent, that of UDP-glucuronosyl transferase (lARC, 1979). 

UDP-glucuronosyl transferase (UGT2B7) Oxazepam, ketoprofen, estradiol, morphine 50, 51... 

Intestinal monoamine oxidase (MAO) metabolizes drugs such as sumatriptan,31 phenylephrine,32 and other amine-containing drugs. A number of hydrolytic and phase II enzymes, such as acetyl transferases, glutathione-S-transferases, methyl transferases, sulfo transferases, and UDP-glucuronosyl transferases, are also present in the intestinal mucosa (see Table 2.2). The amounts of metabolic enzymes decrease... 

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