Enhanced susceptibility of HLA-mediated ticlopidine-induced idiosyncratic hepatotoxicity by CYP2B6 polymorphism in Japanese

Noritaka Ariyoshi, Yukako Iga, Koji Hirata, Yasunori Sato, Go Miura, Itsuko Ishii, Seiji Nagamori, Mitsukazu Kitada

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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 80z of the inferred haplotypes in both control (n=81) and case (n=22) subjects, the prevalence was apparently different: control, *1AA>*6BA>*1HA>*1J and case, *1JA>*1HA>*1AA>*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.-2320TÀC. 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;95zCI, 8.08-196.0, Po0.001). 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.

Original languageEnglish
Pages (from-to)298-306
Number of pages9
JournalDrug Metabolism And Pharmacokinetics
Issue number3
Publication statusPublished - 2010 Jan 1



  • CYP2B6
  • HLA
  • Haplotype
  • Interethnic difference
  • Metabolic activation
  • Ticlopidine-induced hepatotoxicity

ASJC Scopus subject areas

  • Pharmacology
  • Pharmaceutical Science
  • Pharmacology (medical)

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