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  • Title: Enhanced susceptibility of HLA-mediated ticlopidine-induced idiosyncratic hepatotoxicity by CYP2B6 polymorphism in Japanese.
    Author: Ariyoshi N, Iga Y, Hirata K, Sato Y, Miura G, Ishii I, Nagamori S, Kitada M.
    Journal: Drug Metab Pharmacokinet; 2010; 25(3):298-306. PubMed ID: 20610889.
    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.
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