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

Pharmacogenet Genomics. 2007 Dec;17(12):1091-100. doi: 10.1097/FPC.0b013e3282f1f12b.


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.

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B / genetics*
  • ATP Binding Cassette Transporter, Subfamily B / metabolism
  • ATP-Binding Cassette Transporters / genetics*
  • ATP-Binding Cassette Transporters / metabolism
  • Aged
  • Aged, 80 and over
  • Alanine Transaminase / metabolism
  • Alzheimer Disease / drug therapy
  • Alzheimer Disease / genetics
  • Alzheimer Disease / metabolism
  • Animals
  • Biological Transport, Active
  • Cholinesterase Inhibitors / adverse effects*
  • Cholinesterase Inhibitors / metabolism
  • Female
  • Humans
  • LLC-PK1 Cells
  • Liver / drug effects*
  • Liver / injuries
  • Liver / metabolism
  • Male
  • Middle Aged
  • Nootropic Agents / adverse effects
  • Nootropic Agents / metabolism
  • Pharmacogenetics
  • Polymorphism, Single Nucleotide
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Swine
  • Tacrine / adverse effects*
  • Tacrine / metabolism
  • Transfection


  • ATP Binding Cassette Transporter, Subfamily B
  • ATP-Binding Cassette Transporters
  • Cholinesterase Inhibitors
  • Nootropic Agents
  • RNA, Messenger
  • Recombinant Proteins
  • Tacrine
  • multidrug resistance protein 3
  • Alanine Transaminase