Reader TTS

ABSTRACT Genetic risk factors for ticlopidine-induced hepatotoxicity were determined in 22 Japanese patients with ticlopidine-induced hepatotoxicity and 85 Japanese patients who tolerated

ticlopidine therapy without experiencing adverse reactions. There was a significant correlation between ticlopidine-induced hepatotoxicity and five human leukocyte antigen (HLA) alleles:

HLA-A*3303, HLA-B*4403, HLA-Cw*1403, HLA-DRB1*1302 and HLA-DQB1*0604 (corrected probability (_P_)-value (_Pc_)<0.01). In particular HLA-A*3303 was present in 15 (68%) of the 22 patients

with ticlopidine-induced hepatotoxicity and in 12 (14%) of the 85 ticlopidine-tolerant patients (odds ratio, 13.04; 95% confidence interval (CI), 4.40–38.59; the corrected _P_-value

(_Pc_)=1.24 × 10–5). HLA-A*3303 was present in 12 (86%) of the 14 patients with ticlopidine-induced cholestatic hepatotoxicity (odds ratio, 36.50; 95% CI, 7.25–183.82, _Pc_=7.32 × 10–7).

Ticlopidine-induced severe cholestatic hepatotoxicity occurred more frequently in subjects with HLA-A*3303 and its haplotype in Japanese patients. These findings may explain the high

incidence of ticlopidine-induced hepatotoxicity in Japanese patients mediated via an immune-mediated mechanism. Access through your institution Buy or subscribe This is a preview of

subscription content, access via your institution ACCESS OPTIONS Access through your institution Subscribe to this journal Receive 6 print issues and online access $259.00 per year only

$43.17 per issue Learn more Buy this article * Purchase on SpringerLink * Instant access to full article PDF Buy now Prices may be subject to local taxes which are calculated during checkout

ADDITIONAL ACCESS OPTIONS: * Log in * Learn about institutional subscriptions * Read our FAQs * Contact customer support SIMILAR CONTENT BEING VIEWED BY OTHERS THE ANCESTRAL HAPLOTYPE

MARKERS HLA -A3 AND B7 DO NOT INFLUENCE THE LIKELIHOOD OF ADVANCED HEPATIC FIBROSIS OR CIRRHOSIS IN _HFE_ HEMOCHROMATOSIS Article Open access 13 May 2023 _MARC1_ P.A165T VARIANT IS

ASSOCIATED WITH DECREASED MARKERS OF LIVER INJURY AND ENHANCED ANTIOXIDANT CAPACITY IN AUTOIMMUNE HEPATITIS Article Open access 23 December 2021 PHARMACOGENOMIC LANDSCAPE OF THE THAI

POPULATION FROM GENOME SEQUENCING OF 949 INDIVIDUALS Article Open access 28 December 2024 REFERENCES * Jacobson AK . Platelet ADP receptor antagonists: ticlopidine and clopidogrel. _Best

Pract Res Clin Hematol_ 2004; 17: 55–64. Article  CAS  Google Scholar  * Takikawa H . Lessons from ticlopidine-induced liver injury. _Hepatol Res_ 2005; 33: 193–194. Article  PubMed  Google

Scholar  * Mizushima M, Iwata N, Fujimoto TT, Ishikawa K, Fujimura K . Patients characteristics in ticlopidine hydrochloride-induced liver injury: case–control study. _Hepatol Res_ 2005; 33:

234–240. Article  CAS  PubMed  Google Scholar  * Veldhuyzen van Zanten SJO, McCormick CW . Antinuclear antibody-positive ticlopidine-induced hepatitis. _Can J Gastroenterol_ 1996; 10:

231–232. Article  Google Scholar  * Tsai M-H, Tsai S-L, Chen T-C, Liaw Y-F . Ticlopidine-induced cholestatic hepatitis with anti-nuclear antibody in serum. _J Formos Med Assoc_ 2000; 99:

866–869. CAS  PubMed  Google Scholar  * Tsutsui H, Terano Y, Sakagami C, Hasegawa I, Mizoguchi Y, Morisawa S . Drug-specific T cells derived from patients with drug-induced allergic

hepatitis. _J Immunol_ 1992; 149: 706–716. CAS  PubMed  Google Scholar  * Kalgutkar AS, Gardner I, Obach RS, Shaffer CL, Callegari E, Henne KR _et al_. A comprehensive listing of

bioactivation pathways of organic functional groups. _Curr Drug Metab_ 2005; 6: 161–225. Article  CAS  PubMed  Google Scholar  * López Garcia MP, Dansette PM, Valadon P, Amar C, Beaune PH,

Gueng-Erich FP _et al_. Human-liver cytochrome P-450 expressed in yeast as tools for reactive-metabolite formation studies. Oxidative activation of tienilic acid by cytochrome P-450 2C9 and

2C10. _Eur J Biochem_ 1993; 213: 223–232. Article  PubMed  Google Scholar  * López-Garcia MP, Dansette MP, Mansuy D . Thiophene derivatives as new mechanism-based inhibitors of cytochromes

P-450: inactivation of yeast-expressed human liver cytochrome P-450 2C9 by tienilic acid. _Biochemistry_ 1994; 33: 166–175. Article  PubMed  Google Scholar  * Dansette PM, Bonierbale E,

Minoletti C, Beaune PH, Pessayre D, Mansuy D . Drug-induced immunotoxicity. _Eur J Drug Metab Pharmacokinet_ 1998; 23: 443–451. Article  CAS  PubMed  Google Scholar  * Kaplowitz N, DeLeve LD

. _Drug-Induced Liver Disease_. Marcel Dekker: New York, 2003. Google Scholar  * Ieiri I, Kimura M, Irie S, Urae A, Otsubo K, Ishizaki T . Interaction magnitude, pharmacokinetics and

pharmacodynamics of ticlopidine in relation to _CYP2C19_ genotypic status. _Pharmacogenet Genom_ 2005; 15: 851–859. Article  CAS  Google Scholar  * Tateishi T, Kumai T, Watanabe M, Nakura H,

Tanaka M, Kobayashi S . Ticlopidine decreases the _in vivo_ activity of CYP2C19 as measured by omeprazole metabolism. _Br J Clin Pharmacol_ 1999; 47: 454–457. Article  CAS  PubMed  PubMed

Central  Google Scholar  * Ha-Duong N-T, Dijols S, Macherey A-C, Goldstein JA, Dansette PM, Mansuy D . Ticlopidine as a selective mechanism-based inhibitor of human cytochrome P450 2C19.

_Biochemistry_ 2001; 40: 12112–12122. Article  CAS  PubMed  Google Scholar  * Richter T, Mürdter TE, Heinkele G, Pleiss J, Tatzel S, Schwab M _et al_. Potent mechanism-based inhibition of

human CYP2B6 by clopidogrel and ticlopidine. _J Pharmacol Exp Ther_ 2004; 308: 189–197. Article  CAS  PubMed  Google Scholar  * Turpeinen M, Tolonen A, Uusitalo J, Jalonen J, Pelkonen O,

Laine K . Effect of clopidogrel and ticlopidine on cytochrome P450 2B6 activity as measured by bupropion hydroxylation. _Clin Pharmacol Ther_ 2005; 77: 553–559. Article  CAS  PubMed  Google

Scholar  * Ko JW, Desta Z, Soukhova NV, Tracy T, Flockhart DA . _In vitro_ inhibition of the cytochrome P450 (CYP450) system by the antiplatelet drug ticlopidine: potent effect on CYP2C19

and CYP2D6. _Br J Clin Pharmacol_ 2000; 49: 343–351. Article  CAS  PubMed  PubMed Central  Google Scholar  * Boissonnat P, de Lorgeril M, Perroux V, Salen P, Batt AM, Barthelemy JC _et al_.

A drug interaction study between ticlopidine and cyclosporin in heart transplant recipients. _Eur J Clin Pharmacol_ 1997; 53: 39–45. Article  CAS  PubMed  Google Scholar  * Dreiem A, Fonnum

F . Thiophene is toxic to cerebellar granule cells in culture after bioactivation by rat liver enzymes. _Neuro Toxicol_ 2004; 25: 959–966. CAS  Google Scholar  * Kurosaki M, Takagi H, Mori M

. HLA-A33/B44/DR6 is highly related to intrahepatic cholestasis induced by tiopronin. _Dig Dis Sci_ 2000; 45: 1103–1108. Article  CAS  PubMed  Google Scholar  * Andrade RJ, Lucena MI,

Alonso A, García-Cortes M, García-Ruiz E, Benitez R _et al_. HLA class II genotype influences the type of liver injury in drug-induced idiosyncratic liver disease. _Hepatology_ 2004; 39:

1603–1612. Article  CAS  PubMed  Google Scholar  * O'Donohue J, Oien KA, Donaldson P, Underhill J, Clare M, MacSween RNM _et al_. Co-amoxiclav jaundice: clinical and histological

features and HLA class II association. _Gut_ 2000; 47: 717–720. Article  CAS  PubMed  PubMed Central  Google Scholar  * Berson A, Freneaux E, Larrey D, Lepage V, Douay C, Mallet C _et al_.

Possible role of HLA in hepatotoxicity. An exploratory study in 71 patients with drug-induced idiosyncratic hepatitis. _J Hepatol_ 1994; 20: 336–342. Article  CAS  PubMed  Google Scholar  *

Pirmohamed M . Genetic factors in the predisposition to drug-induced hypersensitivity reactions. _J Am Assoc Pharm Sci_ 2006; 8: E20–E26. CAS  Google Scholar  * Saito S, Ota S, Yamada E,

Inoko H, Ota M . Allele frequencies and haplotypic associations defined by allelic DNA typing at HLA class I and class II loci in the Japanese population. _Tissue Antigens_ 2000; 56:

522–529. Article  CAS  PubMed  Google Scholar  * Cao K, Hollenbach J, Shi X, Shi W, Chopek M, Fernández-Viña MA . Analysis of the frequencies of HLA-A, B, and C alleles and haplotypes in the

five major ethnic groups of the United States reveals high levels of diversity in these loci and contrasting distribution patterns in these populations. _Hum Immunol_ 2001; 62: 1009–1030.

Article  CAS  PubMed  Google Scholar  * Danan G, Benichou C . Causality assessment of adverse reactions to drugs I. A novel method based on the conclusions of international consensus

meetings: application to drug-induced liver injuries. _J Clin Epidemiol_ 1993; 46: 1323–1330. Article  CAS  PubMed  Google Scholar  Download references ACKNOWLEDGEMENTS We thank all of the

patients who agreed to take part in this study. We also thank Dr Kingo Fujimura (Professor, Hiroshima University, Faculty of Medicine), Dr Takaaki Isshiki (Professor, Teikyo University,

Department of Medicine), Dr Tsutomu Imaizumi (Professor, Kurume University School of Medicine), Dr Hideo Kusuoka (Vice Director, Osaka National Hospital), Dr Takahito Sone (Director, Ogaki

Municipal Hospital), Dr Genki Mizukoshi (Nippon Medical School), Dr Masayuki Taniguchi (Associate Professor, Jikei University School of Medicine Daisan Hospital), Dr Satoshi Hirose

(Assistant Professor, University of Fukui Hospital) and Dr Hiroyuki Takashima (Teaching Assistant, Shiga University of Medical Science) for patient recruitment and data collection, as well

as Dr Masayuki Yamamoto (Professor, Center for Tsukuba Advanced Research Alliance), Dr Noritaka Ariyoshi (Associate Professor, Chiba University School of Medicine), ADME/TOX Research

Institute of Daiichi Pure Chemicals Co., Ltd, and Mitsubishi Kagaku Bio-Clinical Laboratory Inc. for genotyping analyses. AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Product Lifecycle

Management Department, Daiichi, Tokyo, Japan K Hirata, M Yamamoto & Y Okutani * Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine, Gunma, Japan H

Takagi * PMS and Product Information Management Department, Daiichi, Tokyo, Japan T Matsumoto * R&D Division, Drug Safety Research Laboratory, Daiichi, Tokyo, Japan T Nishiya & K

Mori * R&D Division, Drug Metabolism and Physicochemistry Research Laboratory, Daiichi, Tokyo, Japan S Shimizu & H Masumoto Authors * K Hirata View author publications You can also

search for this author inPubMed Google Scholar * H Takagi View author publications You can also search for this author inPubMed Google Scholar * M Yamamoto View author publications You can

also search for this author inPubMed Google Scholar * T Matsumoto View author publications You can also search for this author inPubMed Google Scholar * T Nishiya View author publications

You can also search for this author inPubMed Google Scholar * K Mori View author publications You can also search for this author inPubMed Google Scholar * S Shimizu View author publications

You can also search for this author inPubMed Google Scholar * H Masumoto View author publications You can also search for this author inPubMed Google Scholar * Y Okutani View author

publications You can also search for this author inPubMed Google Scholar CORRESPONDING AUTHOR Correspondence to K Hirata. ADDITIONAL INFORMATION DUALITY OF INTEREST This study was supported

by Daiichi Pharmaceutical Co., Ltd. RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Hirata, K., Takagi, H., Yamamoto, M. _et al._ Ticlopidine-induced

hepatotoxicity is associated with specific human leukocyte antigen genomic subtypes in Japanese patients: a preliminary case–control study. _Pharmacogenomics J_ 8, 29–33 (2008).

https://doi.org/10.1038/sj.tpj.6500442 Download citation * Received: 30 August 2006 * Revised: 01 January 2007 * Accepted: 01 January 2007 * Published: 06 March 2007 * Issue Date: February

2008 * DOI: https://doi.org/10.1038/sj.tpj.6500442 SHARE THIS ARTICLE Anyone you share the following link with will be able to read this content: Get shareable link Sorry, a shareable link

is not currently available for this article. Copy to clipboard Provided by the Springer Nature SharedIt content-sharing initiative KEYWORDS * ticlopidine * hepatotoxicity * human leukocyte

antigen