Disease relevance of Ugt2b4

• 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 Ugt2b4

• 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 Ugt2b4

• The PB-like inducers, 2,2',4,4',5, 5'-hexachlorobiphenyl (HCB) and 1,1-dichloro-2, 2-bis(p-chlorophenyl)ethane (o,p-DDD), proportionally induced the CYP2B1/2B2 and UDPGT genes and activated the plasmid (HCB = PB > DDD) [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 Ugt2b4

• This work describes the purification and characterization of a 4-HBP UDPGT from rat liver microsomes and, furthermore, provides evidence that suggests that this UDPGT is different from another UDPGT previously shown to react with 4-HBP and chloramphenicol [10].
• 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 [11].
• Expression driven by the SV40 promoter produced enzymatically active UDPGT in COS-7 cells cultured in vitro [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 Ugt2b4 with chemical compounds

• The 4-HBP UDPGT was shown to catalyze the glucuronidation of 4-HBP, 4-methylumbelliferone, and p-nitrophenol but did not react with testosterone, androsterone, morphine, chloramphenicol, 4-hydroxycoumarin, or 7-methoxycoumarin [10].
• The apparent Km of 4-HBP UDPGT for 4-HBP was determined to be 0.26 mM and for UDPGA was 1.0 mM [10].
• A phenobarbital-inducible rat hepatic microsomal UDP-glucuronosyltransferase (UDPGT) that catalyzes the glucuronidation of 4-hydroxybiphenyl (4-HBP) has been purified to homogeneity [10].
• Here we show that this strain-dependent polymorphism and unusual endocrine regulation extend to PB induction of phase II enzymes UGT2B1 uridine diphosphate-glucuronosyl transferase (UDPGT), PB-inducible aldehyde dehydrogenase (ALDH), and glutathione transferases Ya1 and Ya2 (GSTYa1 and GSTYa2) [14].
• UDPGT isoform V (elution pH 7.5) from Wistar (RHA) rats is active toward bilirubin and 4'-hydroxydimethylaminoazobenzene [1].

Analytical, diagnostic and therapeutic context of Ugt2b4

• The UDPGT isoenzymes were purified utilizing Chromatofocusing, column isoelectric focusing, and UDP-hexanolamine Sepharose 4B affinity chromatography [15].
• 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 [16].
• 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 [17].

References