Uridine Diphosphoglucuronyl Transferase Research Articles

Gilbert??s Syndrome and Drug Metabolism

Gilbert's syndrome is an inherited disorder which is characterised by unconjugated hyperbilirubinaemia. In patients with Gilbert's syndrome, both bilirubin clearance and in vitro hepatic microsomal uridine diphosphoglucuronyl transferase (UDPGT) activity are reduced. In addition, there is evidence suggesting impaired hepatic uptake of bilirubin in Gilbert's syndrome. Glucuronidation of a number of substrates appears to be impaired in Gilbert's syndrome, but the significance of the reported changes in oxidation and acetylation are less clear.

Bilirubin Uridine Diphospho-glucuronyltransferase in Rat Liver Microsomes: Genetic Variation and Maturation

Extract: Optimal conditions for the in vitro assay of bilirubin uridine diphospho- (UDP) glu-curonyltransferase activity in rat liver microsomes are described. Solvent partitioning was used to separate the conjugated from nonconjugated bilirubin, thus avoiding dependency on the rate of coupling with diazotized sulfanilic acid for the distinction between bilirubin and its conjugated form. The inclusion of uridine diphospho-N-ace-tylglucosamine (UDPNAG) in the reaction mixture permitted the rate of conjugation of bilirubin by fresh rat liver homogenates and microsomes to occur at greater saturation of the available enzyme with the substrates bilirubin and UDP-glucuronic acid. Liver microsomes, isolated in 0.15 M KC1, increased their activity for bilirubin conjugation and decreased their dependency on UDPNAG during the first 10 days of storage at — 15°. Chromatographic separation of the azo pigments of the conjugated bilirubin gave evidence to suggest that bilirubin monoglucuronide was the initial product and bilirubin diglucuronide appeared in increasing amounts in more prolonged incubations. These results suggested that bilirubin monoglucuronide can be intermediate to the formation of bilirubin diglucuronide. Bilirubin UDP-glucuronyltrans-ferase activity in hepatic microsomes of adult homozygous Gunn rats was not demonstrable. In microsomes of heterozygous Gunn rats and normal Wistar and Sprague-Dawley rats bilirubin UDP-glucuronyltransferase activity was found to be 31.0 and 58.0 μg bilirubin conjugated/mg microsomal N/30 min, respectively. Measurements in developing rats indicated that the maturation in enzyme activity occurred by at least two distinct means: increase of specific activity of the microsomes, and an increase in the content of microsomes per gram of liver (Table IV). Speculation: A method for quantitative measurement of bilirubin UDP-glucuronyltransferase activity applicable to samples obtained by needle biopsy has been needed. The method described in this report meets this need and may permit more precise differential diagnosis of retention jaundice of infancy and childhood and especially the “physiologic” jaundice of the newborn.

Phenobarbital for neonatal jaundice

T H I S C O M M E N T A R Y is prompted by an increasing number of inquiries as to whether it is now indicated to treat hyperbilirubinemia with phenobarbital during the first week of life. In 1968 Catz and Yaffee 1 demonstrated that the conjugation and excretion of bilirubin could be increased significantly in newborn animals by giving sodium barbital daily to them at birth, or to their mothers before birth. Bilirubin is taken up by the parenchymal cells of the liver and excreted into the bile after glucuronide esterification. The glucuronide-conjugating reaction is mediated by the microsomal enzyme uridine diphosphoglucuronyl transferase; the activity of this enzyme, measured in vitro, is low in fetuses and newborns of several species, including humans. The immaturity of this enzyme system is thus a partial explanation for the transient or physiologic hyperbilirubinemia observed in newborn and premature infants and contributes to the hyperbilirubinemia associated with other causes of jaundice, such as sepsis and hemolytic anemia. A number of attempts have now been made to evaluate the effect of phenobarbital on accelerating the bilirubin-conjugating enzyme activity in human fetuses and infants.

DEFICIENCY OF HEPATIC ORGANIC ANION-BINDING PROTEIN AS A POSSIBLE CAUSE OF NON-HÆMOLYTIC UNCONJUGATED HYPERBILIRUBINÆMIA IN THE NEWBORN

The biochemical defect responsible for neonatal non-hæmolytic unconjugated hyperbilirubinæmia ("physiological" jaundice) in man is believed to be immaturity of uridine diphosphoglucuronyl transferase. An alternate hypothesis is that neonatal jaundice results from defective hepatic uptake of bilirubin due to deficiency of an intracellular organic anion-binding protein. The development of two hepatic cytoplasmic organic anion acceptor proteins, Y and Z, was investigated in guineapigs of various ages. Relative deficiency of Y, the major binding protein, was seen in fetal and newborn animals.