Pharmacogenetics of Gilbert's syndrome.
Gilbert's syndrome is characterized by mild unconjugated nonhemolytic hyperbilirubinemia, which does not lead to hepatic inflammation, fibrosis, chronic liver disease or liver failure. Almost 100 years after its clinical description, it was linked to a genetic variant of the human bilirubin UDP-glucuronosyltransferase (UGT1A1), UGT1A1 (*)28, found in approximately 40% of Caucasoid individuals. Over 113 UGT1A1 variants have since been reported, leading to a continuous spectrum from mild hyperbilirubinemia to life-threatening jaundice. UGT1A variants are evolutionary diverse and occur in the context of haplotypes combining different variants within the promoter, the 5 exons, as well as introns of the UGT1A1 gene, and also in combination with other UGT1A genes expressed in the liver and the extrahepatic gastrointestinal tract. The variation of glucuronidation hidden behind Gilbert's syndrome impacts drug therapy, which includes the well-characterized examples of irinotecan and atazanavir. The prediction of unwanted drug reactions associated with Gilbert's syndrome will improve drug safety, therapeutic individualization and impact the drug-development process.
Strassburg
Christian P
CP
Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany. strassburg.christian@mh-hannover.de
D000818:Animals; D001663:Bilirubin / Q000378:metabolism; D064420:Drug-Related Side Effects and Adverse Reactions / Q000201:enzymology / Q000235:genetics*; D014644:Genetic Variation; D005878:Gilbert Disease / Q000201:enzymology / Q000235:genetics / Q000378:metabolism; D014453:Glucuronosyltransferase / Q000235:genetics*; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics; D004364:Pharmaceutical Preparations / Q000378:metabolism; D010597:Pharmacogenetics
D004364:Pharmaceutical Preparations; D014453:Glucuronosyltransferase; D001663:Bilirubin