Enhanced susceptibility of HLA-mediated ticlopidine-induced idiosyncratic hepatotoxicity by CYP2B6 polymorphism in Japanese.
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.
Ariyoshi
Noritaka
N
Division of Pharmacy, University Hospital, Chiba University School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba, Japan. ariyoshi@ho.chiba-u.ac.jp
Iga
Yukako
Y
Hirata
Koji
K
Sato
Yasunori
Y
Miura
Go
G
Ishii
Itsuko
I
Nagamori
Seiji
S
Kitada
Mitsukazu
M
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
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