Tacrine-induced liver damage: an analysis of 19 candidate genes

Alfirevic, Ana; Mills, Tracy; Carr, Daniel F.; Barratt, Bryan J.; Jawaid, Ansar; Sherwood, James; Smith, Jeremy; Tugwood, Jonathan; Hartkoorn, Ruben C.; Owen, Andrew; Park, Kevin B.; Pirmohamed, Munir

doi:10.1097/fpc.0b013e3282f1f12b

Cited by 38 publications

(21 citation statements)

References 49 publications

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“…In fact, ITZ is a potential inhibitor of MDR1 (Gupta et al, 1991;Takara et al, 1999;Iida et al, 2001) and MDR3. Furthermore, tacrine, which often increases LFTs, may also have an inhibitory effect on MDR3; its risk of hepatotoxicity was particularly high in humans carrying some variants of the MDR3 gene (Alfirevic et al, 2007). The in vitro experimental system used in the present study may be useful in determining the inhibitory effect of various compounds on MDR3 function.…”

Section: Discussionmentioning

confidence: 96%

Itraconazole-Induced Cholestasis: Involvement of the Inhibition of Bile Canalicular Phospholipid Translocator MDR3/ABCB4

Yoshikado

Takada

Yamamoto³

et al. 2010

Mol Pharmacol

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Biliary secretion of bile acids and phospholipids, both of which are essential components of biliary micelles, are mediated by the bile salt export pump (BSEP/ABCB11) and multidrug resistance 3 P-glycoprotein (MDR3/ABCB4), respectively, and their genetic dysfunction leads to the acquisition of severe cholestatic diseases. In the present study, we found two patients with itraconazole (ITZ)-induced cholestatic liver injury with markedly high serum ITZ concentrations. To characterize the effect of ITZ on bile formation in vivo, biliary bile acids and phospholipids were analyzed in ITZ-treated rats, and it was revealed that biliary phospholipids, rather than bile acids, were drastically reduced in the presence of clinically relevant concentrations of ITZ. Moreover, by using MDR3-expressing LLC-PK1 cells, we found that MDR3-mediated efflux of [ 14 C]phosphatidylcholine was significantly reduced by ITZ. In contrast, BSEP-mediated transport of [ 3 H]taurocholate was not significantly affected by ITZ, which is consistent with our in vivo observations. In conclusion, this study suggests the involvement of the inhibition of MDR3-mediated biliary phospholipids secretion in ITZ-induced cholestasis. Our approach may be useful for analyzing mechanisms of drug-induced cholestasis and evaluating the cholestatic potential of clinically used drugs and drug candidates.

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Section: Discussionmentioning

confidence: 96%

Itraconazole-Induced Cholestasis: Involvement of the Inhibition of Bile Canalicular Phospholipid Translocator MDR3/ABCB4

Yoshikado

Takada

Yamamoto³

et al. 2010

Mol Pharmacol

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“…It is marketed worldwide under the trade name Cognex. The main disadvantage of tacrine is its relatively high hepatotoxicity 98 . There is an effort underway to find less toxic derivatives of tacrine 99 .…”

Section: Inhibitors Of the α-Anionic Sitementioning

confidence: 99%

Cholinesterases, a Target of Pharmacology and Toxicology

Pohanka¹

2011

Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub

320

219

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Background. Cholinesterases are a group of serine hydrolases that split the neurotransmitter acetylcholine (ACh) and terminate its action. Of the two types, butyrylcholinesterase and acetylcholinesterase (AChE), AChE plays the key role in ending cholinergic neurotransmission. Cholinesterase inhibitors are substances, either natural or man-made that interfere with the break-down of ACh and prolong its action. Hence their relevance to toxicology and pharmacology.Methods and Results. The present review summarizes current knowledge of the cholinesterases and their inhibition. Particular attention is paid to the toxicology and pharmacology of cholinesterase-related inhibitors such as nerve agents (e.g. sarin, soman, tabun, VX), pesticides (e.g. paraoxon, parathion, malathion, malaoxon, carbofuran), selected plants and fungal secondary metabolites (e.g. aflatoxins), drugs for Alzheimer's disease (e.g. huperzine, metrifonate, tacrine, donepezil) and Myasthenia gravis (e.g. pyridostigmine) treatment and other compounds (propidium, ethidium, decamethonium).Conclusions. The crucial role of the cholinesterases in neural transmission makes them a primary target of a large number of cholinesterase-inhibiting drugs and toxins. In pharmacology, this has relevance to the treatment of neurodegenerative disorders.

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“…At present, cholinesterase inhibitors are one of the most prescribed drug classes for AD treatment (Senol et al 2011); however, these drugs cause many side effects (Dunn et al 2000;Alfirevic et al 2007). In consequence, finding new sources for the safest and most effective drugs against this disease becomes relevant.…”

Section: Discussionmentioning

confidence: 99%

“…The few agents approved by the U.S. Federal Drug Administration (FDA) for the treatment of AD have only modest effectiveness in terms of modifying clinical symptoms, and none appear to affect disease progression or prevention (Pasinetti 2012). In addition to their low therapeutic effectiveness, these drugs can cause serious side effects (Dunn et al 2000;Alfirevic et al 2007).…”

Section: Introductionmentioning

confidence: 99%

Anti-inflammatory, antioxidant and anti-acetylcholinesterase activities of Bouvardia ternifolia: potential implications in Alzheimer’s disease

et al. 2015

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Bouvardia ternifolia has been used medicinally to treat inflammation. In the present study, we investigate the anti-Alzheimer's potential effect of the hydroalcoholic extract of B. ternifolia through evaluation of anti-inflammatory and antioxidant activities, quantification of the percentage inhibition of acetylcholinesterase activity, protection effect against β-amyloid fibrillar-induce neurotoxicity, and the identification of the main constituents. Our results show that B. ternifolia extract and ethyl acetate fraction induced anti-inflammatory effects by reducing inflammation by >70 %, while antioxidant test revealed significant IC50 values for flavonoid content fraction (30.67 ± 2.09 μg/ml) and ethyl acetate fraction (42.66 ± 0.93 μg/ml). The maximum inhibition of acetylcholinesterase was exhibited by scopoletin content fraction (38.43 ± 3.94 %), while ethyl acetate fraction exerted neuroprotective effect against β-amyloid peptide (83.97 ± 5.03 %). Phytochemical analysis, showed the presence of 3-O-quercetin glucopyranoside (415 mg/g), rutin (229.9 mg/g), ursolic and oleanolic acid (54 and 20.8 mg/g respectively), 3-O-quercetin rhamnopyranoside (12.8 mg/g), chlorogenic acid (9.5 mg/g), and scopoletin (1.38 mg/g). Our findings support the use of B. ternifolia since the extract induced significant neuroprotection against β-amyloid peptide, anti-inflammatory, antioxidant and anti-acetylcholinesterase effects that could be attributed to its contents of polyphenols, coumarins, and triterpenes, and encourage further studies for development of this extract as therapeutic agent in treatment of Alzheimer's disease.

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Tacrine-induced liver damage: an analysis of 19 candidate genes

Cited by 38 publications

References 49 publications

Itraconazole-Induced Cholestasis: Involvement of the Inhibition of Bile Canalicular Phospholipid Translocator MDR3/ABCB4

Itraconazole-Induced Cholestasis: Involvement of the Inhibition of Bile Canalicular Phospholipid Translocator MDR3/ABCB4

Cholinesterases, a Target of Pharmacology and Toxicology

Anti-inflammatory, antioxidant and anti-acetylcholinesterase activities of Bouvardia ternifolia: potential implications in Alzheimer’s disease

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