Combined glutathione-S-transferase M1 and T1 genetic polymorphism and tacrine hepatotoxicity

Background Glutathione conjugation of tacrine reactive metabolites depends in part on the activity of glutathione-S-transferases (GST), of which two i sozymes (GST Mi and GST T1) are polymorphically expressed. Objective and methods: To determine whether GST M1, GST T1, and the combine d GST M1 and GST T1 null genotypes predict individual susceptibility to tac rine hepatotoxicity, 141 patients with mild to moderate Alzheimer's disease treated with tacrine mere genotyped, Results During the treatment period, 52 patients had elevated alanine amino transferase (ALT) levels at feast three times the upper limit of normal, wh ereas 89 patients had normal ALT values (less than or equal to upper limit of normal). Both groups were comparable in demographic and clinical charact eristics. Twenty-eight patients were found to be GST T1-negative (20%; with a 95% confidence interval [95% CI] from 13% to 27%), and 68 patients (48%; 95% CI from 40% to 57%) were GST M1-negative. The combined GST M1-T1 null gene type nas observed in 18 patients (13%; 95% CI from 7% to 18%) of whom 13 had an elevated plasma ALT at least three times the upper Limit of norma l during the study period. Although the cumulative percentage of elevated p lasma ALT tended to be higher in the GST M1 null genotype, neither GST M1 n or GST T1 alone could predict individual susceptibility to tacrine hepatoto xicity, Multivariate Cox hazards model showed that the association of the G ST M1-T1 null genotype was an independent risk factor of hepatotoxicity Conclusions: The presence of combined alleles M1 and T1 deficiencies in glu tathione-S-transferase genes increases the susceptibility to tacrine hepato toxicity.