Disease relevance of Ugt2a1

• Gunn rats are a mutant strain of Wistar rats that have unconjugated hyperbilirubinemia due to absence of hepatic uridine diphosphate-glucuronosyltransferase (UDPGT; EC. 2.4.1.17) activity toward bilirubin [1].
• The inbred homozygous Gunn rat is also deficient in UDPGT, exhibits unconjugated hyperbilirubinemia, and is an excellent animal model of the Crigler-Najjar syndrome [2].
• These results indicate that the effect of SF is similar to those of PB and thyroid hypertrophy seen in the oral 2-week treatment with SF, and may be caused by indirectly elevated TSH levels which resulted from the induction of hepatic UDPGT activity [3].

High impact information on Ugt2a1

• UDPGT isoform I (elution pH 8.7) from Wistar (RHA) and Gunn rats was active toward 4-nitrophenol [1].
• Isoforms II (elution pH 8.4), III (elution pH 8.0), and IV (elution pH 7.8) from Gunn rats had normal UDPGT activities, except that Isoform IV was inactive toward bilirubin [1].
• The corresponding isoform from Gunn rat liver was enzymically inactive but exhibited normal elution pH and mobility on NaDodSO4/polyacrylamide gel electrophoresis (Mr 53,000), and was recognized by a UDPGT-specific antiserum [1].
• The isoform from Gunn rat liver had only 10% of normal UDPGT activity, however UDPGT activity increased to normal upon addition of 15 mM diethylnitrosamine in vitro [1].
• Of the purified enzymes investigated, only 3 alpha-hydroxysteroid UDPGT catalyzed the glucuronidation of 4-aminobiphenyl. alpha-Naphthylamine and beta-naphthylamine conjugations were catalyzed by 3 alpha-hydroxysteroid, 17 beta-hydroxysteroid, and 3-methylcholanthrene-inducible p-nitrophenol UDPGTs [4].

Biological context of Ugt2a1

• These studies suggest that flunitrazepam binds rather selectively to the morphine binding site of morphine UDPGT and may prove to be a useful probe for this enzyme [5].
• T3 UDPGT activity showed a discontinuous variation, which completely matched the genetic heterogeneity in androsterone glucuronidation in Wistar rats [6].
• These observations suggest that UDP-glucuronosyltransferase (UDPGT), EC2.4.1.17, mediates the in vivo biotransformation of AZT to GAZT [7].
• In rats of all genotypes the hepatic concentration of UDP glucuronosyltransferase (UDPGT) mRNA was increased at 48 and 96 h after the treatment with 3MC [8].
• Use of various modifiers showed a prominent decrease of UDPGT activity in the later part of gestation with changes in tryptophane residues and amino groups, and no change in activity with modification of thiol groups [9].

Anatomical context of Ugt2a1

• Immunoblot analysis of microsomes from developing rat liver demonstrated that the deficiency in bilirubin and testosterone glucuronidation in the fetus was due to the absence of the UDPGT isoenzyme proteins responsible for these conjugations [10].
• Expression driven by the SV40 promoter produced enzymatically active UDPGT in COS-7 cells cultured in vitro [11].
• The effect of malaria infection on UDP-glucuronosyltransferase (UDPGT) activity was investigated in rat liver microsomes using 3'-azido-3'-deoxythymidine and paracetamol [12].
• CONCLUSION: Transplants of small intestine with known UDPGT activity partially corrected the deficiency in Gunn rats and allayed the hyperbilirubinemia [2].
• Steroid glucuronidation was investigated in solubilized female rat and rabbit liver microsomes and in preparations of UDP-glucuronsyltransferase (UDPGT) activity resolved from these organelles [13].

Associations of Ugt2a1 with chemical compounds

• UDPGT isoform V (elution pH 7.5) from Wistar (RHA) rats is active toward bilirubin and 4'-hydroxydimethylaminoazobenzene [1].
• Chromatofocusing chromatography showed that flunitrazepam bound only to fractions containing active morphine UDPGT, and no binding to 4-hydroxybiphenyl UDPGT was observed [5].
• Because flunitrazepam is an effective photoaffinity label for benzodiazepine receptors, studied were performed in solubilized rat hepatic microsomes and with partially purified preparations of morphine UDPGT to determine the enhancement of flunitrazepam inhibition and binding to morphine UDPGT promoted by exposure to UV light [5].
• Parallel to the chemoprotection experiments, the modulation of the activities of cytochrome P4501A2, glutathione-S-transferase (GST) and UDP glucuronosyltransferase (UDPGT) by GC juice, GT and BITC was studied [14].
• Although the basal UDP-glucuronyltransferase (UDPGT) activity with either p-nitrophenol (pNP) or hydroxybiphenyl (HBP) as substrate did not differ significantly, the in-vitro PB- or beta NF-induced activity was higher in pv cells [15].

Analytical, diagnostic and therapeutic context of Ugt2a1

• The UDPGT isoenzymes were purified utilizing Chromatofocusing, column isoelectric focusing, and UDP-hexanolamine Sepharose 4B affinity chromatography [16].
• The activity of hepatic glutathione S-transferase (GST) and UDP-glucuronyl transferase (UDPGT) and the level of glutathione (GSH) were estimated at 0, 45 and 90 days of treatment as well as 28 days after cessation of treatment [17].
• The Michaelis-Menten kinetic parameters (Km and Vmax) associated with the formation of 4Me7OHC and APAP glucuronides demonstrated that the immobilization had not significantly affected the enzymatic activity of the UDPGT relative to the non-immobilized enzyme [18].

References