Molecular and genetic association of interleukin-6 in tacrine-induced hepatotoxicity.
BACKGROUND
Tacrine, an anticholinesterase used to treat Alzheimer's disease (AD), leads to an increase in serum alanine aminotransferase (ALT) levels. The factors determining individual susceptibility are largely unknown. The purpose of this study was to investigate genetic predisposition.


METHODS
Rats were administered single dose tacrine (3-40 mg/kg). After 6 and 24 h, hepatic gene expression was determined using the affymetrix rat U34A microarray. On the basis of the gene expression data, the IL6 gene was identified as a potential candidate for tacrine transaminitis susceptibility. Sixty-nine patients with AD on tacrine with or without transaminitis were genotyped for 17 IL6 polymorphisms.


RESULTS
Serum aspartate aminotransferase levels in rats increased after tacrine (40 mg/kg) administration. Forty-six and 29 genes showed significant upregulation at 6 and 24 h, respectively, after administration, including the IL-6-regulated acute phase response genes alpha2-macroglobulin, fibronectin and haptoglobin. Five of the 17 IL6 polymorphisms studied in AD patients showed an association (P<0.05) with transaminitis [ALT>2 x upper limit of normal (ULN)]. An association existed between maximum ALT and area under curve for ALT over 15 weeks and an intronic polymorphism (P<0.01) and a 3'-variable nucleotide tandem repeat (P<0.05). Multilocus haplotype analysis showed one haplotype (which included the -597A, -572G, -174G and variable nucleotide tandem repeat-D alleles) had a frequency of 0.1 in patients with ALT values >2 x ULN, whereas it was absent in patients with ALT less than 2 x ULN (P=0.0093, Pcorrected=0.049).


CONCLUSIONS
The IL6 genotype may act as a predisposing factor for tacrine transaminitis. This, however, requires further confirmatory functional studies. The role of acute dosing rodent models in identifying candidate genes associated with drug-induced liver injury in man deserves further study.
Carr
Daniel F
DF
Department of Pharmacology and Therapeutics, University of Liverpool, Liverpool, UK.
Alfirevic
Ana
A
Tugwood
Jonathan D
JD
Barratt
Bryan J
BJ
Sherwood
James
J
Smith
John
J
Pirmohamed
Munir
M
Park
B Kevin
BK
D000410:Alanine Transaminase / Q000097:blood / Q000187:drug effects; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000201:enzymology; D000818:Animals; D056486:Chemical and Drug Induced Liver Injury; D020869:Gene Expression Profiling; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics* / Q000494:pharmacology; D008107:Liver Diseases / Q000201:enzymology; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D010277:Parasympathomimetics / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013619:Tacrine / Q000633:toxicity*
D015850:Interleukin-6; D010277:Parasympathomimetics; D013619:Tacrine; D000410:Alanine Transaminase