No Contribution of the ABCB11 p.444A Polymorphism in Japanese Patients with Drug-Induced Cholestasis

Tatehiro Kagawa, Shunji Hirose, Yoshitaka Arase, Akira Oka, Kazuya Anzai, Kota Tsuruya, Koichi Shiraishi, Reiko Orii, Satsuki Ieda, Takahide Nakazawa, Kengo Tomita, Ryota Hokari, Soichiro Miura, Hirotoshi Ebinuma, Hidetsugu Saito, Tsuneo Kitamura, Yoshinori Horie, Chiaki Okuse, Mitsuru Wasada, Hidetoshi InokoMasahiro Tohkin, Yoshiro Saito, Keiko Maekawa, Hajime Takikawa, Tetsuya Mine

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Abstract

European studies have revealed that the ABCB11 c.1331T>C (V444A) polymorphism (rs2287622) C-allele frequency is higher among patients with drug-induced cholestasis. Given the low incidence of this disease, however, this association has not been sufficiently elucidated. We aimed to investigate the significance of this polymorphism in Japanese patients. We determined ABCB11 V444A polymorphism frequencies and HLA genotypes in two independent drug-induced cholestasis cohorts. Expression and taurocholate transport activity of proteins from 444A variants were analyzed using Madin-Darby canine kidney II cells. In cohort 1 (n = 40), the V444A polymorphism C-allele frequency (66%) was lower than that in controls (n = 190, 78%), but this difference was not significant (P = 0.09). In cohort 2 (n = 119), comprising patients with cholestatic (n = 19), hepatocellular (n = 74), and mixed (n = 26) liver injuries, the C-allele frequency was lower among patients with cholestatic liver injury (68%) than among those with hepatocellular (75%) or mixed liver injury (83%), although this difference was not significant. In cohort 1, HLA-A∗0201 was observed more frequently in patients (22%) than in controls [11%; P = 0.003; odds ratio, 2.4 (95% confidence interval, 1.4-4.0)]. Taurocholate transport activity of 444A-encoded protein was significantly lower than that of 444V-encoded protein (81% of 444V, P < 0.05) because of the reduced protein stability. In conclusion, ABCB11 444A had slightly reduced transport activity, but it did not contribute to the occurrence of drug-induced cholestasis in Japanese patients. Therefore, genetic susceptibility to acquired cholestasis may differ considerably by ethnicity.

Original languageEnglish
Pages (from-to)691-697
Number of pages7
JournalDrug Metabolism and Disposition
Volume43
Issue number5
DOIs
Publication statusPublished - 2015 May 1

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ASJC Scopus subject areas

  • Pharmacology
  • Pharmaceutical Science

Cite this

Kagawa, T., Hirose, S., Arase, Y., Oka, A., Anzai, K., Tsuruya, K., Shiraishi, K., Orii, R., Ieda, S., Nakazawa, T., Tomita, K., Hokari, R., Miura, S., Ebinuma, H., Saito, H., Kitamura, T., Horie, Y., Okuse, C., Wasada, M., ... Mine, T. (2015). No Contribution of the ABCB11 p.444A Polymorphism in Japanese Patients with Drug-Induced Cholestasis. Drug Metabolism and Disposition, 43(5), 691-697. https://doi.org/10.1124/dmd.114.061325