Mechanisms of benzarone and benzbromarone-induced hepatic toxicity

Kaufmann, Priska; Török, Michael; Hänni, Anya; Roberts, P. J.; Gasser, Rodolfo; Krähenbühl, Stephan

doi:10.1002/hep.20634

Cited by 159 publications

(121 citation statements)

References 44 publications

(41 reference statements)

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“…It decreases mitochondrial membrane potential, as well as state 3 oxidation and respiratory control ratio, uncouples oxidative phosphorylation, and inhibits b oxidation. Benzarone increases the production of ROS, as well as the leakage of cytochrome C, with final induction of mitochondrial permeability transition [97] . Troglitazone, a PPAR agonist, causes hepatocyte injury by dissipating the mitochondrial transmembrane potential, which favors superoxide g eneration, thioredoxin oxidation and activation of the kinase-1-dependent apoptosis signaling pathway [98] .…”

Section: Examples Of Liver Damage Induced By Commonly Used Drugsmentioning

confidence: 99%

Biochemical mechanisms in drug-induced liver injury: Certainties and doubts

Grattagliano

Bonfrate

Diogo

et al. 2009

WJG

122

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Drug-induced liver injury is a significant and still unresolved clinical problem. Limitations to knowledge about the mechanisms of toxicity render incomplete the detection of hepatotoxic potential during preclinical development. Several xenobiotics are lipophilic substances and their transformation into hydrophilic compounds by the cytochrome P-450 system results in production of toxic metabolites. Aging, preexisting liver disease, enzyme induction or inhibition, genetic variances, local O 2 supply and, above all, the intrinsic molecular properties of the drug may affect this process. Necrotic death follows antioxidant consumption and oxidation of intracellular proteins, which determine increased permeability of mitochondrial membranes, loss of potential, decreased ATP synthesis, inhibition of Ca 2+ -dependent ATPase, reduced capability to sequester Ca 2+ within mitochondria, and membrane bleb formation. Conversely, activation of nucleases and energetic participation of mitochondria are the main intracellular mechanisms that lead to apoptosis. Non-parenchymal hepatic cells are inducers of hepatocellular injury and targets for damage. Activation of the immune system promotes idiosyncratic reactions that result in hepatic necrosis or cholestasis, in which different HLA genotypes might play a major role. This review focuses on current knowledge of the mechanisms of drug-induced liver injury and recent advances on newly discovered mechanisms of liver damage. Future perspectives including new frontiers for research are discussed.

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Section: Examples Of Liver Damage Induced By Commonly Used Drugsmentioning

confidence: 99%

Biochemical mechanisms in drug-induced liver injury: Certainties and doubts

Grattagliano

Bonfrate

Diogo

et al. 2009

WJG

122

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“…These results were attributed to the higher CYP2C9 activity levels in PHH5/6/9 and PHH5/6/9-iPS-HLCs compared with those in PHH1/2/12 and PHH1/2/12-iPS-HLCs. Because it is also known that benzbromarone causes mitochondrial toxicity (12), an assay of mitochondrial membrane potential was performed in benzbromarone-treated PHHs and PHH-iPS-HLCs (Fig. 3F).…”

Section: Phh-ips-hlcs Retained Donor-specific Drug Metabolism Capacitmentioning

confidence: 99%

Prediction of interindividual differences in hepatic functions and drug sensitivity by using human iPS-derived hepatocytes

Takayama¹,

Morisaki²,

Kuno³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

171

161

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Interindividual differences in hepatic metabolism, which are mainly due to genetic polymorphism in its gene, have a large influence on individual drug efficacy and adverse reaction. Hepatocyte-like cells (HLCs) differentiated from human induced pluripotent stem (iPS) cells have the potential to predict interindividual differences in drug metabolism capacity and drug response. However, it remains uncertain whether human iPSC-derived HLCs can reproduce the interindividual difference in hepatic metabolism and drug response. We found that cytochrome P450 (CYP) metabolism capacity and drug responsiveness of the primary human hepatocytes (PHH)-iPSHLCs were highly correlated with those of PHHs, suggesting that the PHH-iPS-HLCs retained donor-specific CYP metabolism capacity and drug responsiveness. We also demonstrated that the interindividual differences, which are due to the diversity of individual SNPs in the CYP gene, could also be reproduced in PHH-iPS-HLCs. We succeeded in establishing, to our knowledge, the first PHH-iPS-HLC panel that reflects the interindividual differences of hepatic drugmetabolizing capacity and drug responsiveness.human iPS cells | hepatocyte | CYP2D6 | personalized drug therapy | SNP D rug-induced liver injury (DILI) is a leading cause of the withdrawal of drugs from the market. Human induced pluripotent stem cell (iPSC)-derived hepatocyte-like cells (HLCs) are expected to be useful for the prediction of DILI in the early phase of drug development. Many groups, including our own, have reported that the human iPS-HLCs have the ability to metabolize drugs, and thus these cells could be used to detect the cytotoxicity of drugs that are known to cause DILI (1, 2). However, to accurately predict DILI, it will be necessary to establish a panel of human iPS-HLCs that better represents the genetic variation of the human population because there are large interindividual differences in the drug metabolism capacity and drug responsiveness of hepatocytes (3). However, it remains unclear whether the drug metabolism capacity and drug responsiveness of human iPS-HLCs could reflect those of donor parental primary human hepatocytes (PHHs). To address this issue, we generated the HLCs differentiated from human iPSCs which had been established from PHHs (PHH-iPS-HLCs). Then, we compared the drug metabolism capacity and drug responsiveness of PHH-iPS-HLCs with those of their parental PHHs, which are genetically identical to the PHH-iPS-HLCs.Interindividual differences of cytochrome P450 (CYP) metabolism capacity are closely related to genetic polymorphisms, especially single nucleotide polymorphisms (SNPs), in CYP genes (4). Among the various CYPs expressed in the liver, CYP2D6 is responsible for the metabolism of approximately a quarter of commercially used drugs and has the largest phenotypic variability, largely due to SNPs (5). It is known that certain alleles result in the poor metabolizer phenotype due to a decrease of CYP2D6 metabolism. Therefore, the appropriate dosage for drugs that are metabolized ...

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“…7 Finally, compound 5 (benzbromarone) has been used in humans as a uricosuric agent for patients suffering from gout. 32 However, its use has been largely restricted due to rare but serious treatment-induced hepatotoxicity. 32 The monosodium urate crystals associated with gout have been reported to induce p38 activity, so despite the rare hepatotoxicity observed during treatment with benzbromarone (~1:17,000), it is possible that there could be an additional p38 inhibition-dependent benefit to benzbromarone treatment in patients with gout.…”

Section: Discussionmentioning

confidence: 99%

Discovery and Characterization of a Biologically Active Non–ATP-Competitive p38 MAP Kinase Inhibitor

et al. 2016

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Mitogen-activated protein kinase (MAPK) p38 is part of a broad and ubiquitously expressed family of MAPKs whose activity is responsible for mediating an intracellular response to extracellular stimuli through a phosphorylation cascade. p38 is central to this signaling node and is activated by upstream kinases while being responsible for activating downstream kinases and transcription factors via phosphorylation. Dysregulated p38 activity is associated with numerous autoimmune disorders and has been implicated in the progression of several types of cancer. A number of p38 inhibitors have been tested in clinical trials, with none receiving regulatory approval. One characteristic shared by all of the compounds that failed clinical trials is that they are all adenosine triphosphate (ATP)-competitive p38 inhibitors. Seeing this lack of mechanistic diversity as an opportunity, we screened ~32,000 substances in search of novel p38 inhibitors. Among the inhibitors discovered is a compound that is both non-ATP competitive and biologically active in cell-based models for p38 activity. This is the first reported discovery of a non-ATP-competitive p38 inhibitor that is active in cells and, as such, may enable new pharmacophore designs for both therapeutic and basic research to better understand and exploit non-ATPcompetitive inhibitors of p38 activity.

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Mechanisms of benzarone and benzbromarone-induced hepatic toxicity

Cited by 159 publications

References 44 publications

Biochemical mechanisms in drug-induced liver injury: Certainties and doubts

Biochemical mechanisms in drug-induced liver injury: Certainties and doubts

Prediction of interindividual differences in hepatic functions and drug sensitivity by using human iPS-derived hepatocytes

Discovery and Characterization of a Biologically Active Non–ATP-Competitive p38 MAP Kinase Inhibitor

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