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Pharmacogenet Genomics. 2007 Dec;17(12):1091-100.

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

Author information

1
Department of Pharmacology and Therapeutics, The University of Liverpool, Sherrington Building, Ashton Street, Liverpool, UK.

Abstract

OBJECTIVES:

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.

METHODS:

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).

RESULTS:

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.

PMID:
18004213
DOI:
10.1097/FPC.0b013e3282f1f12b
[Indexed for MEDLINE]

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