Ticlopidine-induced hepatotoxicity is associated with specific human leukocyte antigen genomic subtypes in Japanese patients: a preliminary case–control study

Hirata, Koji; Takagi, Hitoshi; Yamamoto, Masaru; Matsumoto, Takayuki; Nishiya, Takayoshi; Mori, Kazuhiko; Shimizu, Shinji; Masumoto, Hiroshi; Okutani, Yukihiro

doi:10.1038/sj.tpj.6500442

Cited by 172 publications

(67 citation statements)

References 27 publications

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“…The DRB1*1501-DQB1*0602 association has also been reported in previous studies (Hautekeete et al, 1999;O'Donohue et al, 2000). A few HLA genotypes were shown to associate strongly with particular types of DILI: HLA-B*5701 with flucloxacillin-induced DILI in northern Europeans (odds ratio, 80.6) (Daly et al, 2009) and HLA-A*3303 with ticlopidine-induced cholestatic DILI in Japanese individuals (odds ratio, 36.5) (Hirata et al, 2008). These observations strongly indicate an immune-mediated mechanism in the occurrence of DILI.…”

Section: Discussionsupporting

confidence: 72%

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

et al. 2015

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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.

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Section: Discussionsupporting

confidence: 72%

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

et al. 2015

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“…However, when put in light of its strong association with HLA A*33:03, a number of investigative avenues become clear. 48 For example, naive T-cells from volunteers expressing this allele can be primed to ticlopidine in order to investigate the nature of the drug-antigen in vitro. 74,83 Unfortunately, in vitro models cannot reproduce all the complex pathways involved in iDILI.…”

Section: A Future Direction For Idilimentioning

confidence: 99%

The chemical, genetic and immunological basis of idiosyncratic drug–induced liver injury

et al. 2015

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Idiosyncratic drug reactions can be extremely severe and are not accounted for by the regular pharmacology of a drug. Thus, the mechanism of idiosyncratic drug–induced liver injury (iDILI), a phenomenon that occurs with many drugs including β-lactams, anti-tuberculosis drugs and non-steroidal anti-inflammatories, has been difficult to determine and remains a pressing issue for patients and drug companies. Evidence has shown that iDILI is multifactorial and multifaceted, which suggests that multiple cellular mechanisms may be involved. However, a common initiating event has been proposed to be the formation of reactive drug metabolites and covalently bound adducts. Although the fate of these metabolites are unclear, recent evidence has shown a possible link between iDILI and the adaptive immune system. This review highlights the role of reactive metabolites, the recent genetic innovations which have provided molecular targets for iDILI, and the current literature which suggests an immunological basis for iDILI.

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“…In addition, excess bleeding is observed with the combination of aspirin and P2Y12 ADP receptor antagonists 6,7,9) , since these platelet activation pathways are involved not only in pathologic thrombosis but also in protective hemostasis 1) . A higher incidence of hepatic side effects with the use of thienopyridine P2Y12 ADP receptor antagonists in Japanese patients 10) , due to race-specific haplotype 11) , also limits the use of these P2Y12 ADP receptor antagonists in Japan. Anti-GP b/ a agents, which can inhibit platelet aggregation and reduce thrombotic vascular events after percutaneous coronary intervention (PCI), were proven to induce excess bleeding in Japanese patients and thus have not been approved in Japan 12) .…”

Section: Introductionmentioning

confidence: 99%

Safety and Exploratory Efficacy of the Novel Thrombin Receptor (PAR-1) Antagonist SCH530348 for Non-ST-Segment Elevation Acute Coronary Syndrome

Goto

Yamaguchi

Ikeda

et al. 2010

JAT

103

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Aim: A previous phase 2 study of patients undergoing non-urgent PCI treated with SCH530348 plus aspirin and clopidogrel tended to reduce MACE without increased bleeding. This study evaluated the safety of SCH530348 in Japanese patients with NSTE ACS. Methods: Subjects (117), in whom PCI was planned, received standard-of-care (aspirin, ticlopidine, and heparin) and were randomized 4:1 to receive either SCH530348 (20 or 40 mg loading dose followed by 1 mg/d or 2.5 mg/d for 60 days) or placebo. The key safety endpoint was TIMI major and minor bleeding in the PCI cohort (n 92). The key exploratory efficacy endpoint was MACE and death within 60 days. Addition of SCH530348 to standard-of-care did not significantly increase the rate of TIMI major and minor bleeding (or non-TIMI bleeding) in the primary cohort. Results: Incidence (non-MACE) and discontinuation of AEs were similar across groups. PCI subjects treated with SCH530348 plus standard-of-care experienced a significant reduction in periprocedural MI compared with standard-of-care alone (16.9% vs 42.9%, respectively; p 0.013). There were no deaths or any other MACE. Conclusion: SCH530348 added to standard-of-care did not result in excess bleeding in Japanese subjects with NSTE ACS but significantly reduced the incidence of periprocedural MI in subjects undergoing urgent PCI. J Atheroscler Thromb, 2010; 17:156-164.

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Ticlopidine-induced hepatotoxicity is associated with specific human leukocyte antigen genomic subtypes in Japanese patients: a preliminary case–control study

Cited by 172 publications

References 27 publications

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

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

The chemical, genetic and immunological basis of idiosyncratic drug–induced liver injury

Safety and Exploratory Efficacy of the Novel Thrombin Receptor (PAR-1) Antagonist SCH530348 for Non-ST-Segment Elevation Acute Coronary Syndrome

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