TY - JOUR
T1 - Enhanced susceptibility of HLA-mediated ticlopidine-induced idiosyncratic hepatotoxicity by CYP2B6 polymorphism in Japanese
AU - Ariyoshi, Noritaka
AU - Iga, Yukako
AU - Hirata, Koji
AU - Sato, Yasunori
AU - Miura, Go
AU - Ishii, Itsuko
AU - Nagamori, Seiji
AU - Kitada, Mitsukazu
N1 - Funding Information:
Received; March 2, 2010, Accepted; March 23, 2010 *To whom correspondence should be addressed: Noritaka ARIYOSHI, Ph.D., Division of Pharmacy & Clinical Research Center, University Hospital, Chiba University School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba, 260–8677, Japan. E-mail: ariyoshi＠ho.chiba-u.ac.jp This study was supported in part by a grant from The Nakatomi Foundation.
PY - 2010
Y1 - 2010
N2 - 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.
AB - 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.
KW - CYP2B6
KW - HLA
KW - Haplotype
KW - Interethnic difference
KW - Metabolic activation
KW - Ticlopidine-induced hepatotoxicity
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U2 - 10.2133/dmpk.25.298
DO - 10.2133/dmpk.25.298
M3 - Article
C2 - 20610889
AN - SCOPUS:77954279332
SN - 1347-4367
VL - 25
SP - 298
EP - 306
JO - Drug Metabolism and Pharmacokinetics
JF - Drug Metabolism and Pharmacokinetics
IS - 3
ER -