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Combined glutathione‐ S ‐transferase M1 and T1 genetic polymorphism and tacrine hepatotoxicity
Author(s) -
Simon Tabassome,
Becquemont Laurent,
MaryKrause Murielle,
Waziers Isabelle,
Beaune Philippe,
FunckBrentano Christian,
Jaillon Patrice
Publication year - 2000
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1067/mcp.2000.104944
Subject(s) - tacrine , glutathione s transferase , genotype , glutathione , medicine , allele , confidence interval , isozyme , null allele , endocrinology , pharmacology , biology , genetics , gene , biochemistry , enzyme , acetylcholinesterase
Background Glutathione conjugation of tacrine reactive metabolites depends in part on the activity of glutathione‐S ‐transferases (GST), of which two isozymes (GST M1 and GST T1) are polymorphically expressed. Objective and Methods To determine whether GST M1, GST T1, and the combined GST M1 and GST T1 null genotypes predict individual susceptibility to tacrine hepatotoxicity, 141 patients with mild to moderate Alzheimer's disease treated with tacrine were genotyped. Results During the treatment period, 52 patients had elevated alanine aminotransferase (ALT) levels at least three times the upper limit of normal, whereas 89 patients had normal ALT values (≤upper limit of normal). Both groups were comparable in demographic and clinical characteristics. 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 genotype was 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 normal during the study period. Although the cumulative percentage of elevated plasma ALT tended to be higher in the GST M1 null genotype, neither GST M1 nor GST T1 alone could predict individual susceptibility to tacrine hepatotoxicity. Multivariate Cox hazards model showed that the association of the GST M1‐T1 null genotype was an independent risk factor of hepatotoxicity. Conclusions The presence of combined alleles M1 and T1 deficiencies in glutathione‐S ‐transferase genes increases the susceptibility to tacrine hepatotoxicity. (Clin Pharmacol Ther 2000;67:432‐7.) Clinical Pharmacology & Therapeutics (2000) 67 , 432–437; doi: 10.1067/mcp.2000.104944