Enhanced Susceptibility of HLA-mediated Ticlopidine-induced Idiosyncratic Hepatotoxicity by CYP2B6 Polymorphism in Japanese

Summary: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, * 1 J 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 > * 1 J and case, * 1 J > * 1H > * 1A > * 6B. The reporter gene assay for the two SNPs, which comprise the * 1H or * 1 J haplotype, suggested that the * 1H and * 1 J haplotypes may be associated with the increased expression of CYP2B6, probably due to g. − 2320 T > C. Combination analysis of CYP2B6 and human leukocyte antigen (HLA) haplotypes revealed that individuals possessing CYP2B6* 1H or * 1 J 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.