title: Benign elevations in serum aminotransferases and biomarkers of hepatotoxicity in healthy volunteers treated with cholestyramine.
abstract: BACKGROUND
  There are currently no serum biomarkers capable of distinguishing elevations in serum alanine aminotransferase (ALT) that portend serious liver injury potential from benign elevations such as those occurring during cholestyramine treatment. The aim of the research was to test the hypothesis that newly proposed biomarkers of hepatotoxicity would not significantly rise in serum during elevations in serum ALT associated with cholestyramine treatment, which has never been associated with clinically relevant liver injury.
  
  
  METHODS
  In a double-blind placebo-controlled trial, cholestyramine (8g) was administered for 11 days to healthy adult volunteers. Serum from subjects with elevations in alanine aminotransferase (ALT) exceeding three-fold the upper limit of normal (ULN) were utilized for biomarker quantification.
  
  
  RESULTS
  In 11 of 67 subjects, cholestyramine treatment resulted in ALT elevation by >3x ULN (mean 6.9 fold; range 3-28 fold). In these 11 subjects, there was a 22.4-fold mean increase in serum levels of miR-122 relative to baseline, supporting a liver origin of the serum ALT. Significant elevations were noted in mean levels of necrosis biomarkers sorbitol dehydrogenase (8.1 fold), cytokeratin 18 (2.1 fold) and HMGB1 (1.7 fold). Caspase-cleaved cytokeratin 18, a biomarker of apoptosis was also significantly elevated (1.7 fold). A rise in glutamate dehydrogenase (7.3 fold) may support mitochondrial dysfunction.
  
  
  CONCLUSIONS
  All toxicity biomarkers measured in this study were elevated along with ALT, confirming the liver origin and reflecting both hepatocyte necrosis and apoptosis. Since cholestyramine treatment has no clinical liver safety concerns, we conclude that interpretation of the biomarkers studied may not be straightforward in the context of assessing liver safety of new drugs.
authors.forename: Rohit
authors.initials: R
authors.lastname: Singhal
authors.forename: Alison H
authors.initials: AH
authors.lastname: Harrill
authors.forename: Francoise
authors.initials: F
authors.lastname: Menguy-Vacheron
authors.forename: Zaid
authors.initials: Z
authors.lastname: Jayyosi
authors.forename: Hadj
authors.initials: H
authors.lastname: Benzerdjeb
authors.affiliation: The Hamner-University of North Carolina Institute for Drug Safety Sciences, 6 Davis Drive, Research Triangle Park, NC 27709, USA. pwatkins@thehamner.org.
authors.forename: Paul B
authors.initials: PB
authors.lastname: Watkins
mesh_terms: D000410:Alanine Transaminase / Q000097:blood*; D001219:Aspartate Aminotransferases / Q000097:blood*; D002792:Cholestyramine Resin / Q000008:administration & dosage*; D004311:Double-Blind Method; D064368:Healthy Volunteers; D006801:Humans; D008099:Liver / Q000187:drug effects*; D010919:Placebos
chemical_list: D010919:Placebos; D002792:Cholestyramine Resin; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase
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