title: Association of CYP2C9*2 with bosentan-induced liver injury.
abstract: Bosentan (Tracleer) is an endothelin receptor antagonist prescribed for the treatment of pulmonary arterial hypertension (PAH). Its use is limited by drug-induced liver injury (DILI). To identify genetic markers of DILI, association analyses were performed on 56 Caucasian PAH patients receiving bosentan. Twelve functional polymorphisms in five genes (ABCB11, ABCC2, CYP2C9, SLCO1B1, and SLCO1B3) implicated in bosentan pharmacokinetics were tested for associations with alanine aminotransferase (ALT), aspartate aminotransferase (AST), and DILI. After adjusting for body mass index, CYP2C9*2 was the only polymorphism associated with ALT, AST, and DILI (β = 2.16, P = 0.024; β = 1.92, P = 0.016; odds ratio 95% CI = 2.29-∞, P = 0.003, respectively). Bosentan metabolism by CYP2C9*2 in vitro was significantly reduced compared with CYP2C9*1 and was comparable to that by CYP2C9*3. These results suggest that CYP2C9*2 is a potential genetic marker for prediction of bosentan-induced liver injury and warrants investigation for the optimization of bosentan treatment.
authors.affiliation: Department of Bioengineering and Therapeutic Sciences, Institute for Human Genetics, University of California, San Francisco, San Francisco, California, USA.
authors.forename: S M
authors.initials: SM
authors.lastname: Markova
authors.forename: T
authors.initials: T
authors.lastname: De Marco
authors.forename: N
authors.initials: N
authors.lastname: Bendjilali
authors.forename: E A
authors.initials: EA
authors.lastname: Kobashigawa
authors.forename: J
authors.initials: J
authors.lastname: Mefford
authors.forename: J
authors.initials: J
authors.lastname: Sodhi
authors.forename: H
authors.initials: H
authors.lastname: Le
authors.forename: C
authors.initials: C
authors.lastname: Zhang
authors.forename: J
authors.initials: J
authors.lastname: Halladay
authors.forename: A E
authors.initials: AE
authors.lastname: Rettie
authors.forename: C
authors.initials: C
authors.lastname: Khojasteh
authors.forename: D
authors.initials: D
authors.lastname: McGlothlin
authors.forename: A H B
authors.initials: AH
authors.lastname: Wu
authors.forename: W-C
authors.initials: WC
authors.lastname: Hsueh
authors.forename: J S
authors.initials: JS
authors.lastname: Witte
authors.forename: J B
authors.initials: JB
authors.lastname: Schwartz
authors.forename: D L
authors.initials: DL
authors.lastname: Kroetz
mesh_terms: D000410:Alanine Transaminase / Q000378:metabolism; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics* / Q000378:metabolism; D001219:Aspartate Aminotransferases / Q000378:metabolism; D000077300:Bosentan; D056486:Chemical and Drug Induced Liver Injury / Q000201:enzymology / Q000209:etiology*; D065729:Cytochrome P-450 CYP2C9; D065128:Endothelin Receptor Antagonists; D005260:Female; D056726:Genetic Association Studies; D005819:Genetic Markers; D057809:HEK293 Cells; D006801:Humans; D006976:Hypertension, Pulmonary / Q000188:drug therapy*; D027381:Liver-Specific Organic Anion Transporter 1; D008297:Male; D008875:Middle Aged; D000089762:Multidrug Resistance-Associated Protein 2; D027361:Organic Anion Transporters / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D013449:Sulfonamides / Q000009:adverse effects*
chemical_list: C000715087:ABCC2 protein, human; D065128:Endothelin Receptor Antagonists; D005819:Genetic Markers; D027381:Liver-Specific Organic Anion Transporter 1; D000089762:Multidrug Resistance-Associated Protein 2; D027361:Organic Anion Transporters; C503999:SLCO1B1 protein, human; D013449:Sulfonamides; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D000077300:Bosentan