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A lawyer with a drink problem
Published in Tim French, Terry Wardle, The Problem-Based Learning Workbook, 2022
Bilirubin is formed from the breakdown of haem. Unconjugated bilirubin is transported to the liver bound to albumin. It is water insoluble and therefore is not excreted in the urine. Bilirubin conjugated in the liver to bilirubin glucuronide is water soluble. Conjugated bilirubin appears in the urine when plasma levels rise.
Liver Diseases
Published in George Feuer, Felix A. de la Iglesia, Molecular Biochemistry of Human Disease, 2020
George Feuer, Felix A. de la Iglesia
During uptake of the pigment by the liver cell, the bilirubin-albumin complex molecules are first concentrated at the surface of the membranes. After passing into the cell, the bilirubin is separated from albumin inside the membrane with the subsequent formation of glucuronides in the microsomal region. These molecules move across the cell and are concentrated at the canalicular membrane before they are excreted into the bile. The unidirectional nature of this process is essential (Figure 18). Any disturbance of this mechanism produces leaks from the bile canaliculi back into the sinusoids, resulting in jaundice. From the bile canaliculi network, the bile is transported to the common bile duct and then to the gallbladder where it is concentrated and emptied into the duodenum. The bilirubin glucuronide is carried to the large intestine and converted to urobilinogen under the influence of reducing enzymes of chronic bacteria. Most of this urobilinogen is oxidized to urobilin and finally excreted into the stool. The remainder is carried back to the liver by the portal vein and may either be converted to bilirubin glucuronides by the liver cells or excreted into the bile canaliculi unchanged. The glucuronides, as well as any unchanged urobilinogen and urobilin, are carried back to the intestine by the bile, and thus the enterohepatic circulation is completed (Figure 19).
The Role of Conjugating Enzymes in the Biliary Excretion of Bilirubin
Published in Karel P. M. Heirwegh, Stanley B. Brown, Bilirubin, 1982
Histochemical and chemical studies have shown that unconjugated bilirubin, in addition to conjugated bilirubin, accumulates in the livers of patients with obstructive jaundice.117,118 It has been noted that the bilirubin granules are associated with increased β-glucuronidase activity in hepatic parenchymal and Kupffer cells, and it has therefore been postulated that deconjugation of bilirubin glucuronide has occurred.117,118 This hypothesis has been tested in vivo by injecting [14C]bilirubin glucuronide in Gunn rats whose bile ducts have been ligated, and then demonstrating that unconjugated [14C]bilirubin accumulates in the serum.119 These experiments did not, however, indicate that deconjugation had necessarily taken place in the liver or that β-glucuronidase played a role in the process. Further indirect evidence of β-glucuronidase activity in bilirubin metabolism has been given in recent HPLC studies of bile pigments in cholestatic serum120,121 which demonstrate that, although bilirubin diglucuronide is the major pigment in bile, bilirubin monoglucuronide usually predominates in the plasma and unconjugated bilirubin may be increased, in spite of adequate amounts of glucuronyltransferase in the liver.122
The relationship between UGT1A1 gene & various diseases and prevention strategies
Published in Drug Metabolism Reviews, 2022
Dan Liu, Qi Yu, Qing Ning, Zhongqiu Liu, Jie Song
The CN, an autosomal recessive disorder, was first described under the title ‘congenital familial nonhemolytic jaundice with kernicterus’, in 1952, which has two types (Crigler and Najjar 1952). Mutant alleles of the common UGT1A exons 2–5 affect all transcripts generated by the UGT1A locus, both hepatic and extrahepatic, and this was viewed as the reason for the complete absence of bilirubin glucuronide formation in type I CN1. Exon 1 mutations are characteristic of CN2. CN1 have complete absence of UGT1A1 activity, which is a rare and fatal stealth genetic disease. CN2 retain a partial function of this enzyme about 10%, and is less severe with jaundice and usually survive to adulthood without neurological or intellectual disability (Fitzpatrick et al. 2008). More than 70 years after CN was discovered, CN1 remains a morbid and potentially fatal disorder. Liver transplantation is the only successful treatment for CN disorders, but it requires expensive treatment costs and other risks after surgery. Therefore, more treatments for CN are urgently needed to be developed.
Transporter-mediated drug–drug interactions: advancement in models, analytical tools, and regulatory perspective
Published in Drug Metabolism Reviews, 2021
Aishwarya Jala, Srikanth Ponneganti, Devi Swetha Vishnubhatla, Gayathri Bhuvanam, Prithvi Raju Mekala, Bincy Varghese, Pullapanthula Radhakrishnanand, Ramu Adela, Upadhyayula Suryanarayana Murty, Roshan M. Borkar
Conjugated and unconjugated bilirubin are used as a biomarker for OATP1B1transporter. van de Steeg et al. explained that the disruption of hepatic reuptake of bilirubin glucuronide due to OATP1B1 and OATP1B3 deficiencies linked with Rotor type hyperbilirubinemia (van de Steeg et al. 2012). Chu et al. found that increased plasma AUC of conjugated and unconjugated bilirubin in cynomolgus monkey after administration of rifampicin (inhibitor of OATP1B1; Chu et al. 2015). Prueksaritanont et al. conducted a clinical study for translating the observation of cynomolgus monkeys to humans (Prueksaritanont et al. 2017). The authors observed increased plasma AUC of total and conjugated bilirubin after a single administration of rifampicin. Bilirubin is also used as a common marker for hepatotoxicity. Hence, bilirubin is also a biomarker for OATP1B1. It ought to be analyzed in combination with other biomarkers.