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

Simon, T

doi:10.1067/mcp.2000.104944

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

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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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Polymorphisms in glutathione S-transferase can impact oxidative DNA damage, and the M1 and T1 genetic polymorphisms are associated with greater hepatotoxicity.
“Polymorphisms in this enzyme can impact the amount of oxidative DNA damage, and the M1 and T1 genetic polymorphisms are associated with greater hepatotoxicity49.”
From Performance assessment and economic analysis of a human Liver-Chip for predictive toxicology (2022) · cites this paper as [49]

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Glutathione S‐transferase mu genotype (GSTM1*0) in Alzheimer's patients with tacrine transaminitis.
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Self-citation
GlutathioneS-Transferase M1 Null Genotype as a Risk Factor for Carbamazepine-Induced Mild Hepatotoxicity
Ueda, K., Ishitsu, T., Seo, T., Ueda, N., Murata, T., Hori, M., & Nakagawa, K. (2007) · Pharmacogenomics · doi:10.2217/14622416.8.5.435 · Cited by 66
Glutathione S-transferase M1 and T1 polymorphisms and the risk of mild hepatotoxicity induced by carbamazepine in a tunisian population study
Chbili, C., Hassine, A., Fathallah, N., Nouira, M., Salma, N., Ammou, S. B., & Saguem, S. (2018) · BMC Neurology · doi:10.1186/s12883-018-1013-8 · Cited by 10
Running title: GSTM1/GSTT1 defects and troglitazone-induced liver injury
Usui, T., Hashizume, T., Katsumata, T., Yokoi, T., & At, A. (2016)

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

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