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Cited by 122Glutathione Transferases and PolymorphismsPharmacogenetics and Drug MetabolismDrug-Induced Hepatotoxicity and Protection

The DOI matches its Crossref record; 24 of the 25 references it cites were found in a registry or an index.

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

Simon, T·2000·Clinical Pharmacology & Therapeutics
DOI 10.1067/mcp.2000.104944
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Abstract

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 (< or = 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.

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Metadata

Authors
Simon, T.
Affiliations
Inserm (FR)
Corresponding author
Simon, T
ORCID
Simon, T
Venue
Clinical Pharmacology & Therapeutics
Publisher
Wiley
Published
2000-04
Volume
67
Issue
4
Pages
432-437
ISSN
0009-9236 (ISSN-L)
DOI
10.1067/mcp.2000.104944
OpenAlex
W2015114639
Cited by
122
References
25
Citations by year
2025: 4 · 2024: 3 · 2023: 2 · 2022: 6 · 2021: 7 · 2020: 2 · 2019: 2 · 2018: 3 · 2017: 5 · 2016: 4 · 2015: 5 · 2014: 1 · 2013: 6 · 2012: 4
FWCI
0.72
Type
journal article
Language
en
Open access
closed
Locations
  • Clinical Pharmacology & Therapeutics (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Glutathione Transferases and Polymorphisms
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
Keywords
tacrine, hepatotoxicity, glutathione S-transferase M1, glutathione S-transferase T1, genetic polymorphism, Alzheimer's disease, drug-induced liver injury, glutathione conjugation, alanine aminotransferase, pharmacogenetics, drug sensitivity
MeSH terms
Aged, Alleles, Alzheimer Disease, Female, Genotype, Glutathione Transferase, Humans, Isoenzymes, Liver, Liver Function Tests, Male, Parasympathomimetics, Pharmacogenetics, Polymorphism, Genetic, Tacrine, Proportional Hazards Models, Genetic Predisposition to Disease

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