title: Genetic susceptibility to hepatoxicity due to bosentan treatment in pulmonary hypertension.
abstract: BACKGROUND
  Hepatotoxicity is a major side effect of treatment with bosentan in patients with pulmonary hypertension (PH). Bosentan is metabolized by the cytochrome CYP2C9 and inhibits the bile salt export pump, which is encoded by ABCB11. This suggests that genetic variants of CYP2C9 and/or ABCB11 may predispose patients to bosentan-induced liver injury.
  
  
  METHODS
  PH patients with (n = 23) or without (n = 25) an increase of alanine aminotransferase (ALT) or aspartate-aminotransferase (AST) during bosentan therapy were included in our analysis. Functionally relevant alleles of CYP2C9 and 16 representative variants of ABCB11 were genotyped. Data were analyzed using logistic regression.
  
  
  RESULTS
  Variants of ABCB11 were not associated with bosentan-induced liver injury. In contrast, variant alleles of CYP2C9 were more common in patients with elevated transaminases (allele frequency 52%) compared to controls (allele frequency 24%, P = 0.04, odds ratio 3.5, 95% confidence interval 1.01-11.8).
  
  
  CONCLUSIONS
  Our data indicate hepatotoxicity of bosentan from decreased hepatic metabolism due to common variants of CYP2C9.
authors.affiliation: Division of Respiratory Medicine, Department of Internal Medicine, Neurology and Dermatology, University Hospital of Leipzig, Germany.
authors.forename: Hans-Jürgen
authors.initials: HJ
authors.lastname: Seyfarth
authors.affiliation: Division of Gastroenterology and Rheumatology, Department of Internal Medicine, Neurology and Dermatology, University Hospital of Leipzig, Germany.
authors.forename: Nadine
authors.initials: N
authors.lastname: Favreau
authors.affiliation: Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, Department of Internal Medicine, Neurology and Dermatology, University Hospital of Leipzig, Germany.
authors.forename: Carsten
authors.initials: C
authors.lastname: Tennert
authors.affiliation: Division of Gastroenterology and Rheumatology, Department of Internal Medicine, Neurology and Dermatology, University Hospital of Leipzig, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Ruffert
authors.affiliation: Internal Medicine I Carl Gustav Carus University Dresden, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Halank
authors.affiliation: Division of Respiratory Medicine, Department of Internal Medicine, Neurology and Dermatology, University Hospital of Leipzig, Germany.
authors.forename: Hubert
authors.initials: H
authors.lastname: Wirtz
authors.affiliation: Division of Gastroenterology and Rheumatology, Department of Internal Medicine, Neurology and Dermatology, University Hospital of Leipzig, Germany.
authors.forename: Joachim
authors.initials: J
authors.lastname: Mössner
authors.affiliation: Division of Gastroenterology and Rheumatology, Department of Internal Medicine, Neurology and Dermatology, University Hospital of Leipzig, Germany.
authors.forename: Jonas
authors.initials: J
authors.lastname: Rosendahl
authors.affiliation: Integrated Research and Treatment Center Adiposity Diseases, University of Leipzig, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Kovacs
authors.affiliation: Division of Gastroenterology and Rheumatology, Department of Internal Medicine, Neurology and Dermatology, University Hospital of Leipzig, Germany; HELIOS Hospital Schleswig, Germany.
authors.forename: Henning
authors.initials: H
authors.lastname: Wittenburg
mesh_terms: D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000410:Alanine Transaminase / Q000097:blood; D000959:Antihypertensive Agents / Q000009:adverse effects*; D001219:Aspartate Aminotransferases / Q000097:blood; D000077300:Bosentan; D016022:Case-Control Studies; D056486:Chemical and Drug Induced Liver Injury / Q000097:blood / Q000209:etiology / Q000235:genetics*; D065729:Cytochrome P-450 CYP2C9 / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D006976:Hypertension, Pulmonary / Q000188:drug therapy*; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D013449:Sulfonamides / Q000009:adverse effects*
chemical_list: C093491:ABCB11 protein, human; D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters; D000959:Antihypertensive Agents; D013449:Sulfonamides; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D000077300:Bosentan