Tacrine-induced liver damage: an analysis of 19 candidate genes.
OBJECTIVE
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.
Alfirevic
Ana
A
Department of Pharmacology and Therapeutics, The University of Liverpool, Sherrington Building, Ashton Street, Liverpool, UK.
Mills
Tracy
T
Carr
Daniel
D
Barratt
Bryan J
BJ
Jawaid
Ansar
A
Sherwood
James
J
Smith
John C
JC
Tugwood
Jonathan
J
Hartkoorn
Ruben
R
Owen
Andrew
A
Park
Kevin B
KB
Pirmohamed
Munir
M
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics* / Q000378:metabolism; D018528:ATP-Binding Cassette Transporters / Q000235:genetics* / Q000378:metabolism; D000368:Aged; D000369:Aged, 80 and over; D000410:Alanine Transaminase / Q000378:metabolism; D000544:Alzheimer Disease / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001693:Biological Transport, Active; D002800:Cholinesterase Inhibitors / Q000009:adverse effects* / Q000378:metabolism; D005260:Female; D006801:Humans; D018374:LLC-PK1 Cells; D008099:Liver / Q000187:drug effects* / Q000293:injuries / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D018697:Nootropic Agents / Q000009:adverse effects / Q000378:metabolism; D010597:Pharmacogenetics; D020641:Polymorphism, Single Nucleotide; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D013552:Swine; D013619:Tacrine / Q000009:adverse effects* / Q000378:metabolism; D014162:Transfection
D018435:ATP Binding Cassette Transporter, Subfamily B; D018528:ATP-Binding Cassette Transporters; D002800:Cholinesterase Inhibitors; D018697:Nootropic Agents; D012333:RNA, Messenger; D011994:Recombinant Proteins; D013619:Tacrine; C095122:multidrug resistance protein 3; D000410:Alanine Transaminase