Article

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

Department of Pharmacology and Therapeutics, The University of Liverpool, Sherrington Building, Ashton Street, Liverpool, UK.
Pharmacogenetics and Genomics (impact factor: 3.48). 01/2008; 17(12):1091-100. DOI:10.1097/FPC.0b013e3282f1f12b
Source: PubMed

ABSTRACT Tacrine, the first acetylcholinesterase inhibitor used in the treatment of Alzheimer's disease, is associated with transaminase elevation in up to 50% of patients. The mechanism of tacrine-induced liver damage is not fully understood, but earlier studies have suggested that genetic factors may play a role. Our aim was to investigate whether single-nucleotide polymorphisms (SNPs) in 19 candidate genes were associated with tacrine-induced liver damage.
Sixty-nine patients of Caucasian origin treated with tacrine for Alzheimer's disease were investigated by genotyping 241 SNPs in 19 candidate genes potentially related to hepatotoxicity. The association with ABCB4 [which encodes MultiDrug Resistance Protein 3 (MDR3)] was explored in transepithelial transport studies using the ABCB4-transfected pig kidney epithelial cell line (LLC-PK1).
The strongest association between alanine aminotransferase levels and three SNPs within ATP-binding cassette, subfamily B (MDR/TAP), member 4 (ABCB4) (uncorrected P=0.0005) was not significant after adjusting for multiple testing. No association was demonstrated with ATP-binding cassette, subfamily B (MDR/TAP), member 1 (ABCB1) or carnitine O-octanoyltransferase (CROT) which are located adjacent to ABCB4. Using the transepithelial transport system we failed to show a difference in tacrine accumulation between ABCB4-transfected and parental cell lines. The association with ABCB4 warrants further testing using either another population and/or functional studies.

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    Article: Acetylcholinesterase based assay of eleven organophosphorus pesticides: finding of assay limitations
    Miroslav Pohanka, Lucie Drtinova, Kamil Kuca
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    ABSTRACT: The study includes findings about limitations of acetylcholinesterase (AChE) based assay. Eleven organophosphorus pesticides: chlorpyrifos ethyl, chlorpyrifos methyl, DFP, dichlorvos, dimethoate, fenthion, paraoxon ethyl, paraoxon methyl, phosalone, pirimiphos methyl and pirimiphos ethyl were photometrically assayed using AChE as a recognition element. The study was carried out in order to find approachability of AChE based assay. In the first round, common organic solvents were tested for interfering in assay, since samples collection and extraction is a necessary part in samples processing. Isopropanol was found as the most convenient due to minimal inhibition not exceeding 5%. Though all analysed pesticides inhibit AChE in vivo, some of them are toxic after metabolisation. We found AChE based assay approachable for assay of DFP, paraoxons, and dichlorvos. These are oxoforms of organophosphorus pesticides. From thioforms of assayed pesticides, only fenthion was able significantly inhibit AChE in vitro. Electrochemical biosensor with AChE attached on platinum electrode was used for confirmation of interaction pesticide – AChE and complex stability estimation. DFP, paraoxons and dichlorvos were allowed to interact with AChE in biosensor. These pesticides were settled firmly in AChE active site as no spontaneous recovery of AChE activity was observed.
    Intern. J. Environ. Anal. Chem. 01/2012; 92(1):125-132.
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Keywords

19 candidate genes
 
ABCB4 warrants
 
ABCB4-transfected pig kidney epithelial cell line
 
Alzheimer's disease
 
first acetylcholinesterase inhibitor
 
functional studies
 
genetic factors
 
genotyping 241 SNPs
 
member 1
 
member 4
 
multiple testing
 
parental cell lines
 
single-nucleotide polymorphisms
 
strongest association
 
subfamily B
 
tacrine accumulation
 
tacrine-induced liver damage
 
transaminase elevation
 
transepithelial transport studies
 
transepithelial transport system