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UGT1A1 Polymorphisms and Mutations Affect Anticancer Drug Therapy
Published in Sherry X. Yang, Janet E. Dancey, Handbook of Therapeutic Biomarkers in Cancer, 2021
Tristan M. Sissung, Roberto Barbier, Lisa M. Cordes, William D. Figg
Genetic variants in UGT1A1 are also associated with Crigler-Najjar syndrome, a more-severe inherited state of hyperbilirubinemia [2]. Crigler-Najjar Syndrome is a rare disorder affecting the metabolism of bilirubin, and is divided into two types: type I and type II. More than 40 different deleterious mutations distributed both in the unique and common exons of the UGT1A1 gene have been found in Crigler-Najjar syndrome types I and II [66]. Crigler-Najjar syndrome type I is a very rare disease with less than 1 case per million live births, and an autosomal recessive pattern of inheritance [67]. In Crigler-Najjar syndrome type I, most patients have a mutation in one of the common exons (2 to 5) of UGT1A1 and have complete absence of enzyme activity. Thus patients have difficulties conjugating several substrates (i.e. drugs and xenobiotics) [67–70]. A smaller percentage of patients have mutations limited to the bilirubin-specific A1 exon; their conjugation defect is mostly restricted to bilirubin itself [26, 68]. This results in severe hyperbilirubinemia, which is characterized by serum bilirubin levels that usually range from 20–50 mg/dL (the normal range for total bilirubin is 0.1–1.0 mg/dL) [71]. As a result, intense jaundice appears in the first days of life and persists thereafter. Some affected infants die within the first year of life of kernicterus (bilirubin accumulation in the basal ganglia and brainstem nuclei), while others survive with little or no neurologic defect [26, 67, 68, 71–73]. Patients do not respond to phenobarbital treatment, which induces glucuronyl transferase induction, and only traces of unconjugated bilirubin can be found in their bile which is often colorless [71]. Phototherapy is the preferred treatment for Crigler-Najjar type I disease. However, since kernicterus can develop at a later age, phototherapy sometimes becomes inadequate at keeping serum bilirubin levels below 15 mg/dL, at which point liver transplantation may be required [71, 74, 75].
The Role of Kinetic Analysis and Mathematical Modeling in the Study of Bilirubin Metabolism in Vivo
Published in Karel P. M. Heirwegh, Stanley B. Brown, Bilirubin, 1982
E. Anthony Jones, Ewart R. Carson, Paul D. Berk
New insights into the physiology of bilirubin metabolism have been obtained through the application of a multicompartmental model of erythrokinetics.46 In this model, the life cycle of the erythrocyte from its earliest differentiation in the bone marrow to its ultimate senescent death and conversion into bilirubin is represented by 20 compartments arranged in series (Figure 9). The model includes inputs of newly synthesized bilirubin into the plasma from the catabolism of senescent red cells and from ineffective erythropoiesis. Thus, of the three most important sources of bilirubin only hepatic-synthesized bilirubin is not represented. Inherent in the model is the assumption that the plasma concentration of bilirubin varies directly with plasma bilirubin turnover (see Equation 13). Furthermore, the model includes nonphysiologic loss pathways of bilirubin from the plasma due to the removal by phlebotomy of cohorts of circulating red cells of variable age. This model was used in the interpretation of the results of a study in which an attempt was made to lower the plasma bilirubin concentration of an adult patient with encephalopathy associated with the Crigler-Najjar syndrome (Type I congenital nonhemolytic jaundice). The procedure employed was to reduce plasma bilirubin turnover by reducing the contribution from circulating senescent red cells. This was achieved by shortening the mean age of circulating erythrocytes by a program of chronic repeated phlebotomy. In the subject of the investigation an initial conventional study of bilirubin metabolism involving the intravenous injection of a tracer dose of labeled bilirubin indicated that the terminal half-life of the plasma disappearance curve was long, the hepatic bilirubin clearance rate very low and the plasma bilirubin turnover rate normal. Similar data have been obtained in other studies of unconjugated bilirubin metabolism in the Crigler-Najjar syndrome.43,44 Surprisingly, as the patient was subjected to the program of chronic phlebotomy the plasma bilirubin concentration did not decrease in parallel with the fall in plasma bilirubin turnover. Indeed, the plasma bilirubin concentration was maintained by a parallel decrease in hepatic bilirubin clearance. Prior to this study it had been assumed that the plasma bilirubin concentration was dependent on plasma bilirubin turnover in the Crigler-Najjar syndrome. The results of this study showed that this assumption was invalid. Furthermore, the model failed to reproduce experimentally observed data, indicating that the particular model structure adopted was inappropriate. Thus, although the original therapeutic goal of reducing the plasma bilirubin concentration was not achieved by phlebotomy, new knowledge was obtained about the pathophysiology of bilirubin metabolism in the Crigler-Najjar syndrome. This study is an important example of the way in which compartmental modeling can be used for predicting and explaining results of physiological experiments and therapeutic regimes and for the testing of hypotheses.
Pharmaceutical strategies for preventing toxicity and promoting antioxidant and anti-inflammatory actions of bilirubin
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2022
Alessio Nocentini, Alessandro Bonardi, Simone Pratesi, Paola Gratteri, Carlo Dani, Claudiu T. Supuran
Three types of inherited, predominantly unconjugated non-haemolytic hyperbilirubinaemia have been identified according to different levels of UGT1A1 activity, related to protein mutations1,20: Crigler–Najjar syndrome type I (CN1), Arias syndrome type II (CN2) and Gilbert's syndrome (GS). On the other hand, two types of hereditary conjugated jaundice exist, that are the benign Dubin–Johnson and Rotor syndromes21,22.