title: Drug- and Drug Abuse-Associated Hyperbilirubinemia: Experience With Atazanavir.
abstract: Hyperbilirubinemia is a common finding in individuals with a history of substance abuse. Although this may indicate a serious disorder of liver function, this is not always the case. An understanding of bilirubin formation, metabolism, and transport can provide a helpful approach to dealing with these patients. This is typified by studies of patients treated with the antiretroviral drug atazanavir. Atazanavir has been associated with hyperbilirubinemia in as many as one-third of individuals for whom it has been prescribed, evoking concerns of hepatotoxicity. The studies in this report were designed to determine mechanisms by which this occurs. The data show that this drug inhibits the enzyme UDP-glucuronosyl transferase-1A1, responsible for conjugating bilirubin with glucuronic acid. This conjugation step is required for bilirubin excretion into bile, and when it is inhibited, bilirubin refluxes from the liver into the circulation, causing unconjugated hyperbilirubinemia. Other parameters of bilirubin formation, binding to albumin in the circulation, uptake into hepatocytes, and intracellular protein binding in hepatocytes were unaffected by atazanavir. The effect of atazanavir on serum bilirubin levels is reversible, consistent with lack of structural damage to the liver.
authors.affiliation: Marion Bessin Liver Research Center, Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, NY, USA.|Division of Gastroenterology and Liver Diseases, Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, NY, USA.|Department of Genetics, Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, NY, USA.
authors.forename: Jayanta
authors.initials: J
authors.lastname: Roy-Chowdhury
authors.affiliation: Marion Bessin Liver Research Center, Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, NY, USA.|Division of Gastroenterology and Liver Diseases, Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, NY, USA.|Department of Genetics, Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, NY, USA.
authors.forename: Namita
authors.initials: N
authors.lastname: Roy-Chowdhury
authors.affiliation: Marion Bessin Liver Research Center, Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, NY, USA.|Department of Biochemistry, Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, NY, USA.
authors.forename: Irving
authors.initials: I
authors.lastname: Listowsky
authors.affiliation: Marion Bessin Liver Research Center, Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, NY, USA.|Division of Gastroenterology and Liver Diseases, Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, NY, USA.|Department of Anatomy and Structural Biology, Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, NY, USA.
authors.forename: Allan W
authors.initials: AW
authors.lastname: Wolkoff
mesh_terms: D000818:Animals; D000069446:Atazanavir Sulfate / Q000008:administration & dosage / Q000009:adverse effects*; D001663:Bilirubin / Q000097:blood* / Q000378:metabolism; D002478:Cells, Cultured; D005260:Female; D014453:Glucuronosyltransferase / Q000037:antagonists & inhibitors; D005982:Glutathione Transferase / Q000378:metabolism; D017320:HIV Protease Inhibitors / Q000008:administration & dosage / Q000009:adverse effects*; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D006932:Hyperbilirubinemia / Q000097:blood / Q000139:chemically induced*; D008297:Male; D017208:Rats, Wistar; D019438:Ritonavir / Q000008:administration & dosage; D019966:Substance-Related Disorders / Q000150:complications; D000099148:UGT1A1 Enzyme
chemical_list: D000069446:Atazanavir Sulfate; D001663:Bilirubin; D014453:Glucuronosyltransferase; D005982:Glutathione Transferase; D017320:HIV Protease Inhibitors; D019438:Ritonavir; D000099148:UGT1A1 Enzyme
keywords: UDP-glucuronosyl transferase; atazanavir; drug toxicity; hyperbilirubinemia; transport