title: Enhanced susceptibility of HLA-mediated ticlopidine-induced idiosyncratic hepatotoxicity by CYP2B6 polymorphism in Japanese.
abstract: Hepatotoxicity is the most frequent adverse drug reaction (ADR) in Japanese treated with ticlopidine (TP). We investigated the relationship between CYP2B6 haplotype and incidence of TP-induced hepatotoxicity in 114 Japanese patients. Although 4 haplotypes (*1A, *1H, *1J and *6B) accounted for more than 80% of the inferred haplotypes in both control (n=81) and case (n=22) subjects, the prevalence was apparently different: control, *1A>*6B>*1H>*1J and case, *1J>*1H>*1A>*6B. The reporter gene assay for the two SNPs, which comprise the *1H or *1J haplotype, suggested that the *1H and *1J haplotypes may be associated with the increased expression of CYP2B6, probably due to g.-2320T>C. Combination analysis of CYP2B6 and human leukocyte antigen (HLA) haplotypes revealed that individuals possessing CYP2B6*1H or *1J with HLA-A*3303 have the highest susceptibility to TP-induced hepatotoxicity (odds ratio, 38.82; 95%CI, 8.08-196.0, P<0.001). Although this is a preliminary case-control study with some limitations, it is the first example that HLA-induced idiosyncratic ADR may be modified by individual variation in CYP activities.
authors.affiliation: Division of Pharmacy, University Hospital, Chiba University School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba, Japan. ariyoshi@ho.chiba-u.ac.jp
authors.forename: Noritaka
authors.initials: N
authors.lastname: Ariyoshi
authors.forename: Yukako
authors.initials: Y
authors.lastname: Iga
authors.forename: Koji
authors.initials: K
authors.lastname: Hirata
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Sato
authors.forename: Go
authors.initials: G
authors.lastname: Miura
authors.forename: Itsuko
authors.initials: I
authors.lastname: Ishii
authors.forename: Seiji
authors.initials: S
authors.lastname: Nagamori
authors.forename: Mitsukazu
authors.initials: M
authors.lastname: Kitada
mesh_terms: D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D001711:Biotransformation / Q000235:genetics; D016022:Case-Control Studies; D056486:Chemical and Drug Induced Liver Injury / Q000453:epidemiology* / Q000235:genetics*; D065702:Cytochrome P-450 CYP2B6; D004789:Enzyme Activation / Q000187:drug effects; D005838:Genotype; D006680:HLA Antigens / Q000235:genetics*; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D007564:Japan / Q000453:epidemiology / Q000208:ethnology; D010089:Oxidoreductases, N-Demethylating / Q000235:genetics*; D010975:Platelet Aggregation Inhibitors / Q000009:adverse effects* / Q000627:therapeutic use; D020641:Polymorphism, Single Nucleotide; D013988:Ticlopidine / Q000009:adverse effects* / Q000627:therapeutic use
chemical_list: D006680:HLA Antigens; D010975:Platelet Aggregation Inhibitors; D001189:Aryl Hydrocarbon Hydroxylases; C585599:CYP2B6 protein, human; D065702:Cytochrome P-450 CYP2B6; D010089:Oxidoreductases, N-Demethylating; D013988:Ticlopidine