Glutathione S-transferase mu genotype (GSTM1*0) in Alzheimer's patients with tacrine transaminitis.
1. Tacrine (1,2,3,4-tetrahydro-9-aminoacridine) which is used in Alzheimer's disease, causes elevation of liver transaminases ('tacrine transaminitis') in 40-50% of patients. This may be related to the formation of a chemically reactive metabolite from tacrine, which can be detoxified in vitro by glutathione. 2. Glutathione-S-transferase mu (GSTM1), a detoxication enzyme, is polymorphically expressed being absent in about 50% of patients. Its role in the detoxication of the reactive metabolite of tacrine is not known. 3. The frequency of the enzyme deficiency (GSTM1*0) has been investigated in patients with tacrine transaminitis using polymerase chain reaction (PCR) to determine whether the GSTM1 status can be used as an absolute predictive factor for susceptibility to tacrine transaminitis. 4. The frequency of the GSTM1*0 genotype in patients with tacrine transaminitis (n = 33; 45.5%) was not significantly different from that in patients treated with tacrine without liver dysfunction (n = 37; 43%), and when compared with all the controls used in the study (n = 167; 56%). 5. The frequency of the GSTM1*0 genotype in patients with Alzheimer's disease (n = 79; 46%) was not significantly different from that in healthy volunteers (n = 121; 59.5%). 6. Our results indicate that the GSTM1 status cannot be used clinically to predict individual susceptibility to tacrine transaminitis, and that patients with the GSTM1*0 genotype are unlikely to have an increased risk of tacrine-induced liver damage. Furthermore, the GSTM1 status was not associated with Alzheimer's disease.
Green
V J
VJ
Department of Pharmacology and Therapeutics, University of Liverpool.
Pirmohamed
M
M
Kitteringham
N R
NR
Knapp
M J
MJ
Park
B K
BK
D000293:Adolescent; D000328:Adult; D000368:Aged; D000544:Alzheimer Disease / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics*; D001483:Base Sequence; D016001:Confidence Intervals; D017931:DNA Primers / Q000737:chemistry; D004587:Electrophoresis, Agar Gel; D005260:Female; D017353:Gene Deletion; D005787:Gene Frequency; D005838:Genotype; D005982:Glutathione Transferase / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D016017:Odds Ratio; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic / Q000235:genetics; D013619:Tacrine / Q000009:adverse effects* / Q000378:metabolism / Q000627:therapeutic use; D000637:Transaminases / Q000187:drug effects / Q000378:metabolism*
D017931:DNA Primers; D013619:Tacrine; D005982:Glutathione Transferase; D000637:Transaminases