Glucuronidation, of bilirubin

Tab. 12.2 Different forms of jaundice classified in relation to the metabolic disorder of bilirubin and glucuronidation of bilirubin...

In this example, investigative studies were conducted to address an issue of unconjugated hyperbilirubinemia in human subjects observed after administration of HIV protease inhibitors indinavir and atazanavir. The proposed hypothesis for hyperbilirubinemia was inhibition of glucuronidation of bilirubin by these two drugs, a key step in the excretion of bilirubin into bile. To test this hypothesis, a panel of HIV protease inhibitors, including atazanavir, indinavir, lopinavir, nelfinavir, ritonavir, and saquinavir, were... 

Glucuronyl transferase (UDP-glncuronate biliru-bin-glucuronyltransferase) (EC 2.4.1.76). Enzyme completely absent. Severe jaundice and brain encephalopathy. Often death in infancy. Conjugation is obligatory for excretion of bilirubin. In a milder form of the disease some enzyme is present, and treatment is possible by administration of phenobar-bital, which stimulates hepatic uptake, conjugation and biliary secretion (as glucuronide) of bilirubin. 

Ethanol has been used recently in obstetrics and in neonatal pediatrics for three principal therapeutic reasons prevention of premature labor, reduction of anticipated neonatal hyperbilirubinemia, and parenteral nutrition. The use of ethanol in the prevention of premature labor is based on its inhibitory effect on uterine activity in early labor it presumably acts by inhibiting the release of oxytocin from the neurohypophysis (Fuchs l., 1967). Ethanol when administered to near-term or term pregnant patients has been shown to reduce hyperbilirubinemia in the neonates (Waltman t l., 1969). Its use has been suggested, therefore, to reduce anticipated hyperbilirubinemia in those neonates in which high serum bilirubin may be expected, such as premature infants. The reduction of bilirubin after ethanol administration is probably due to increased glucuronidation of bilirubin since ethanol has been demonstrated to stimulate a variety of microsomal enzymes in both animals and man (Rubin t l., 1968). 

Type I Crigler-Najjar syndrome is a rare autosomal recessive disorder. It is characterized by severe congenital jaundice (serum bilirubin usually exceeds 20 mg/dL) due to mutations in the gene encoding bilirubin-UGT activity in hepatic tissues. The disease is often fatal within the first 15 months of life. Children with this condition have been treated with phototherapy, resulting in some reduction in plasma bilirubin levels. Phenobarbital has no effect on the formation of bilirubin glucuronides in patients with type I Crigler-Najjar syndrome. A liver transplant may be curative. 

FIGURE 7.3 Structures of bilirubin diglucuronide and the 3- and 6-glucuronides of morphine. 

The synthesis, glucuronidation and hepatic transport of new aromatic congeners of bilirubin have also been followed by an RP-HPLC method. The chemical strucutres of bilirubin derivatives are shown in Fig. 2.160. 

J.O. Brower, D.A. Lightner and A.F. McDonagh, Aromatic congeners of bilirubin synthesis, stereochemistry, glucuronidation and hepatic transport. Tetrahedron 57 (2001) 7813-7827. 

Jl. Jacobsen, J., A chromatographic separation of bilirubin glucuronides from human bile. Acta Chim. Scand. 23, 3023-3026 (1969). 

Schmid, R., Hammaker, L., and Axelrod, J., The enzymatic formation of bilirubin glucuronide. Arch. Biochem. Biophys. 70, 285-288 (1957). 

Alterations in the metabolism of heme. A. Hemolytic jaundice. B. Neonatal jaundice. [Note The enterohepatic circulation of urobilinogen is omitted for simplicity.] BG = bilirubin glucuronide B = bilirubin U = urobilinogen S = stercobilin. 

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