Bilirubin UGT

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.

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. 

This rare inherited disorder also results from mutations in the gene encoding bilirubin-UGT, but some activity of the enzyme is retained and the condition has a more benign course than type I. Serum bilirubin concentrations usually do not exceed 20 mg/dL. Patients with this condition can respond to treatment with large doses of phenobarbital. 

Again, this is caused by mutations in the gene encoding bilirubin-UGT, but approximately 30% of the enzyme s activity is preserved and the condition is entirely harmless. 

Three inherited disorders of bilirubin metabolism are associated with defects in bilirubin UGT-1 activity Gilbert s syndrome, and Crigler-Najjar syndrome types I and II. Dubin-Johnson syndrome is due to a defect in the protein pump that extrudes bilirubin from the hepatocyte... 

Mechanism Decreased bilirubin conjugation, as low bilirubin UGT-1 levels Absent bilirubin conjugation, as no bilirubin UGT-1 levels Markedly decreased bilirubin conjugation, as minimally active bilirubin UGT-1 levels Impaired canalicular excretion of conjugated bilirubin Unknown... 

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. 

Deficiency of UGT leads to ineffective esterification of bihrubin, which in turn results in an unconjugated hyperbUirubinaemia. Reduced bilirubin conjugation, as a result of a decreased or absent UGT activity, is found in a number of acquired conditions and inherited diseases, such as Crigler-Najjar syndrome (types I and II) and Gilbert syndrome. Bilirubin-conjugating activity is also very low in the neonatal liver. 

UGT activity is modulated by various hormones. Excess thyroid hormone and ethinyl oestradiol (but not other oral contraceptives) inhibit bilirubin glucuronidation. In contrast, the combination of progestational and oestrogenic steroids results in increased enzyme activity. Bihrubin glucuronidation can also be inhibited by certain antibiotics (e.g. novobiocin or gentamicin, at serum concentrations exceeding therapeutic levels) and by chronic hepatitis, advanced cirrhosis and Wilson s disease. 

Abbreviations used in text AA, arachidonic acid AhR, aryl hydrocarbon receptor Amt, AhR nuclear translocator BR, bilirubin BV, biliverdin CYP1A1, cytochrome P4501A1 DRE, dioxin responsive element FICZ, 6-formylindolo(3,2b)carbazole HAH, halogenated aromatic hydrocarbon I3C, indole 3-carbinol ICZ, indolo-(3,2,-b)-carbazole PAH, polycyclic aromatic hydrocarbon RAR, retinoic acid receptor TCDD, 2,3,7,8-tetrachlorodi benzo-/>-dioxin Trp, tryptophan UGT 01, UDP-glucuronosy 1 transferase 01... 

AHR ARNT Dioxins, non -ortho PCBs, some PAHs, bilirubin, etc. CYP1A, CYP1B GST, UGT, NQO... 

Biochemical induction studies in rats and primary rat hepatocytes demonstrated that digitoxigenin monodigitoxoside UGT activity could be induced by glucocorticoids, which is consistent with induction of UGT activity via PXR [71], Similarly, hepatic UGT activity versus bilirubin, 1-naphthol, chloramphenicol, thyroxine, and trioodothyronine were induced, and mRNA levels of Ugtlal and la9 were more than 100% increased in mice following PCN treatment [86], By contrast, the PXR... 

UGTs play a significant role in Phase II detoxification of drugs in humans, and are reportedly responsible for more than one-third of all the Phase II metabolism of drugs. UGTs are also important enzymes in maintaining homeostasis of numerous endobiotics such as steroids, bilirubin, bile acids, and thyroid hormones. 

UGTIAI is the UGT principally responsible for bilirubin glucuronidation. There are 60 rare mutations in the UGTIAI gene known to date, but only a few of them occur with a sufficient frequency (> 1%) to represent polymorphisms. 

In an attempt to develop effective UGT inhibitors, transition-state based inhibitors were synthesized taking advantage of the high affinity of UGT for the UDP moiety and the structural requirement for the acceptor substrate, w.w.o)-Triphenylalkyl-UDP derivatives (Fig. 31.40) have been shown to be powerful inhibitors of UGT bilirubin isoform. In the same manner, DMSU was an efficient inhibitor of phenol glucuronidation catalysed by UGT1A6. ... 

---