Ticlopidine, a Cholestatic Liver Injury-Inducible Drug, Causes Dysfunction of Bile Formation via Diminished Biliary Secretion of Phospholipids: Involvement of Biliary-Excreted Glutathione-Conjugated Ticlopidine Metabolites

Yoshikado, Takashi; Takada, Tappei; Yamamoto, Hideaki; Tan, Jeng Kae; Ito, Kousei; Santa, Tomofumi; Suzuki, Hiroshi

doi:10.1124/mol.112.081752

Cited by 17 publications

(8 citation statements)

References 41 publications

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“…37 A study in rats suggests that adducts are formed following metabolism by cytochrome P450 with evidence for toxicity after biliary excretion of glutathione-conjugated metabolites via MRP2-facilitated transport. 38 In previous studies, 22 Japanese patients with ticlopidine DILI showed an association with an HLA haplotype including A*33:03 (odds ratio 13). 39 In line with current observations, the association was strongest with cholestatic cases with 12 out of 14 cases positive for A*33:03.…”

Section: Discussionmentioning

confidence: 93%

Association of Liver Injury From Specific Drugs, or Groups of Drugs, With Polymorphisms in HLA and Other Genes in a Genome-Wide Association Study

et al. 2017

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BACKGROUND & AIMS We performed a genome-wide association study (GWAS) to identify genetic risk factors for drug-induced liver injury (DILI) from licensed drugs without previously reported genetic risk factors. METHODS We performed a GWAS of 862 persons with DILI and 10588 population-matched controls. The first set of cases was recruited prior to May 2009 in Europe (n=137) or the USA (n=274). The second set of cases were identified from May 2009 through May 2013 from international collaborative studies performed in Europe, the USA and South America. For the GWAS, we included only cases of European ancestry associated with a particular drug (but not flucloxacillin or amoxicillin-clavulanate). We used DNA samples from all subjects to analyze human leukocyte antigen (HLA) genes and single nucleotide polymorphisms (SNPs). After the discovery analysis was concluded, we validated our findings using data from 283 European patients with diagnosis of DILI associated with various drugs. RESULTS We associated DILI with rs114577328 (a proxy for A*33:01 a HLA class I allele; odds ratio [OR], 2.7; 95% CI, 1.9–3.8; P=2.4×10−8) and with rs72631567 on chromosome 2 (OR, 2.0; 95% CI, 1.6–2.5; P=9.7×10−9). The association with A*33:01 was mediated by large effects for terbinafine-, fenofibrate-, and ticlopidine-related DILI. The variant on chromosome 2 was associated with DILI from a variety of drugs. Further phenotypic analysis indicated that the association between DILI and A*33:01 was significant, genome wide, for cholestatic and mixed DILI, but not for hepatocellular DILI; the polymorphism on chromosome 2 associated with cholestatic and mixed DILI as well as hepatocellular DILI. We identified an association between rs28521457 (within the LRBA gene) and only hepatocellular DILI (OR, 2.1; 95% CI, 1.6–2.7; P=4.8×10−9). We did not associate any specific drug classes with genetic polymorphisms, except for statin-associated DILI, which was associated with rs116561224 on chromosome 18 (OR=5.4; 95% CI, 3.0–9.5; P=7.1×10−9). We validated the association between A*33:01 terbinafine- and sertraline-induced DILI. We could not validate the association between DILI and rs72631567, rs28521457, or rs116561224. CONCLUSIONS In a GWAS of persons of European descent with DILI, we associated HLA-A*33:01 with DILI due to terbinafine and possibly fenofibrate and ticlopidine. We identified polymorphisms that appear to be associated with DILI from statins, as well as 2 non–drug-specific risk factors.

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Section: Discussionmentioning

confidence: 93%

Association of Liver Injury From Specific Drugs, or Groups of Drugs, With Polymorphisms in HLA and Other Genes in a Genome-Wide Association Study

et al. 2017

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“…Ticlopidine-induced cholestatic liver injury is not fully understood, but is often seen in an idiosyncratic manner. In rats, extensive secretion of glutathione conjugates of ticlopidine by MRP2 altered the bile composition and decreased the biliary secretion of phospholipids, which may contribute to the cholestatic hepatotoxicity of ticlopidine 35 . Furthermore, studies point towards a pivotal role of the adaptive immune system, since ticlopidine stimulated T cells of patients with ticlopidine-induced cholestatic hepatitis in vitro , but not T cells from healthy controls 36 .…”

Section: Discussionmentioning

confidence: 99%

Hepatic 3D spheroid models for the detection and study of compounds with cholestatic liability

Hendriks

Puigvert

Messner

et al. 2016

Sci Rep

127

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Drug-induced cholestasis (DIC) is poorly understood and its preclinical prediction is mainly limited to assessing the compound’s potential to inhibit the bile salt export pump (BSEP). Here, we evaluated two 3D spheroid models, one from primary human hepatocytes (PHH) and one from HepaRG cells, for the detection of compounds with cholestatic liability. By repeatedly co-exposing both models to a set of compounds with different mechanisms of hepatotoxicity and a non-toxic concentrated bile acid (BA) mixture for 8 days we observed a selective synergistic toxicity of compounds known to cause cholestatic or mixed cholestatic/hepatocellular toxicity and the BA mixture compared to exposure to the compounds alone, a phenomenon that was more pronounced after extending the exposure time to 14 days. In contrast, no such synergism was observed after both 8 and 14 days of exposure to the BA mixture for compounds that cause non-cholestatic hepatotoxicity. Mechanisms behind the toxicity of the cholestatic compound chlorpromazine were accurately detected in both spheroid models, including intracellular BA accumulation, inhibition of ABCB11 expression and disruption of the F-actin cytoskeleton. Furthermore, the observed synergistic toxicity of chlorpromazine and BA was associated with increased oxidative stress and modulation of death receptor signalling. Combined, our results demonstrate that the hepatic spheroid models presented here can be used to detect and study compounds with cholestatic liability.

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“…Forty-eight hours later, cells were collected and the membrane vesicles were isolated by a standard method with repeated centrifugation and homogenization. [10] After the expression of mouse Abcg2 protein was confirmed by western blot analysis, the transport studies of [ 14 C]urate (28 μM, American Radiolabeled Chemicals) were performed by a standard protocol for transport assays with membrane vesicles. [11] All other chemicals used in this study were commercially available and of reagent grade.…”

Section: Methodsmentioning

confidence: 99%

ABCG2 Dysfunction Increases Serum Uric Acid by Decreased Intestinal Urate Excretion

Takada

Ichida

Matsuo

et al. 2014

Nucleosides, Nucleotides and Nucleic Acids

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ATP-binding cassette transporter G2 (ABCG2), also known as breast cancer resistance protein (BCRP), is identified as a high-capacity urate exporter and its dysfunction has an association with serum uric acid (SUA) levels and gout/hyperuricemia risk. However, pathophysiologically important pathway(s) responsible for the ABCG2-mediated urate excretion were unknown. In this study, we investigated how ABCG2 dysfunction affected the urate excretion pathways. First, we revealed that mouse Abcg2 mediates urate transport using the membrane vesicle system. The export process by mouse Abcg2 was ATP-dependent and not saturable under the physiological concentration of urate. Then, we characterized the excretion of urate into urine, bile, and intestinal lumen using in vivo mouse model. SUA of Abcg2-knockout mice was significantly higher than that of control mice. Under this condition, the renal urate excretion was increased in Abcg2-knockout mice, whereas the urate excretion from the intestine was decreased to less than a half. Biliary urate excretion showed no significant difference regardless of Abcg2 genotype. From these results, we estimated the relative contribution of each pathway to total urate excretion; in wild-type mice, the renal excretion pathway contributes approximately two-thirds, the intestinal excretion pathway contributes one-third of the total urate excretion, and the urate excretion into bile is minor. Decreased intestinal excretion could account for the increased SUA of Abcg2-knockout mice. Thus, ABCG2 is suggested to have an important role in extra-renal urate excretion, especially in intestinal excretion. Accordingly, increased SUA in patients with ABCG2 dysfunction could be explained by the decreased excretion of urate from the intestine.

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Ticlopidine, a Cholestatic Liver Injury-Inducible Drug, Causes Dysfunction of Bile Formation via Diminished Biliary Secretion of Phospholipids: Involvement of Biliary-Excreted Glutathione-Conjugated Ticlopidine Metabolites

Cited by 17 publications

References 41 publications

Association of Liver Injury From Specific Drugs, or Groups of Drugs, With Polymorphisms in HLA and Other Genes in a Genome-Wide Association Study

Association of Liver Injury From Specific Drugs, or Groups of Drugs, With Polymorphisms in HLA and Other Genes in a Genome-Wide Association Study

Hepatic 3D spheroid models for the detection and study of compounds with cholestatic liability

ABCG2 Dysfunction Increases Serum Uric Acid by Decreased Intestinal Urate Excretion

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