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Glutathione S-transferase m1 and t1 null genotypes increase susceptibility to idiosyncratic drug-induced liver injury.
Hepatology. 2008 Aug; 48(2):588-96.Hep

Abstract

Individual vulnerability to drug-induced liver injury (DILI) might result from deficiencies in the detoxification process, which determines the level of exposure to the reactive metabolite. We evaluated whether a genetically determined reduction in the ability to detoxify electrophilic compounds, such as that expected among individuals with glutathione S-transferase (GST) null genotypes, might play a role in determining the risk for DILI and its clinical expression. Genomic DNA from 154 patients (74 men, 80 women; mean age, 53 years) with a diagnosis of DILI as assessed with the Council for International Organizations of Medical Science scale and 250 sex- and age-matched healthy controls were analyzed. A multiplex polymerase chain reaction-based method was used to detect GSTM1 and GSTT1 gene deletions. Carriers of double GSTT1-M1 null genotypes had a 2.70-fold increased risk of developing DILI compared with noncarriers (odds ratio 2.70, 95% confidence interval 1.45-5.03; P = 0.003). The odds ratio for DILI patients receiving antibacterials, and NSAIDs were 3.52 (P = 0.002), and 5.61 (P = 0.001), respectively. Patients with amoxicillin-clavulanate hepatotoxicity (n = 32) had a 2.81-fold increased risk (P = 0.037). Patients classified by the combined GSTT1 and GSTM1 null genotypes did not differ with regard to the type of injury, clinical presentation, or outcome, except for the predominance of women in the combined null genotype (P < 0.001).

CONCLUSION

The double-null genotype for GSTT1 and GSTM1 might play a role in determining the susceptibility to develop DILI, as a general mechanism that occurs regardless of the type of drug involved, and predominantly in women.

Authors+Show Affiliations

Servicio de Farmacología Clínica, Clinical Pharmacology Service, Liver Unit University Hospital School of Medicine, Málaga, Spain. lucena@uma.esNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

18666253

Citation

Lucena, M Isabel, et al. "Glutathione S-transferase M1 and T1 Null Genotypes Increase Susceptibility to Idiosyncratic Drug-induced Liver Injury." Hepatology (Baltimore, Md.), vol. 48, no. 2, 2008, pp. 588-96.
Lucena MI, Andrade RJ, Martínez C, et al. Glutathione S-transferase m1 and t1 null genotypes increase susceptibility to idiosyncratic drug-induced liver injury. Hepatology. 2008;48(2):588-96.
Lucena, M. I., Andrade, R. J., Martínez, C., Ulzurrun, E., García-Martín, E., Borraz, Y., Fernández, M. C., Romero-Gomez, M., Castiella, A., Planas, R., Costa, J., Anzola, S., & Agúndez, J. A. (2008). Glutathione S-transferase m1 and t1 null genotypes increase susceptibility to idiosyncratic drug-induced liver injury. Hepatology (Baltimore, Md.), 48(2), 588-96. https://doi.org/10.1002/hep.22370
Lucena MI, et al. Glutathione S-transferase M1 and T1 Null Genotypes Increase Susceptibility to Idiosyncratic Drug-induced Liver Injury. Hepatology. 2008;48(2):588-96. PubMed PMID: 18666253.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Glutathione S-transferase m1 and t1 null genotypes increase susceptibility to idiosyncratic drug-induced liver injury. AU - Lucena,M Isabel, AU - Andrade,Raúl J, AU - Martínez,Carmen, AU - Ulzurrun,Eugenia, AU - García-Martín,Elena, AU - Borraz,Yolanda, AU - Fernández,M Carmen, AU - Romero-Gomez,Manuel, AU - Castiella,Agustin, AU - Planas,Ramón, AU - Costa,Joan, AU - Anzola,Sandra, AU - Agúndez,José A G, AU - ,, PY - 2008/7/31/pubmed PY - 2008/9/6/medline PY - 2008/7/31/entrez SP - 588 EP - 96 JF - Hepatology (Baltimore, Md.) JO - Hepatology VL - 48 IS - 2 N2 - UNLABELLED: Individual vulnerability to drug-induced liver injury (DILI) might result from deficiencies in the detoxification process, which determines the level of exposure to the reactive metabolite. We evaluated whether a genetically determined reduction in the ability to detoxify electrophilic compounds, such as that expected among individuals with glutathione S-transferase (GST) null genotypes, might play a role in determining the risk for DILI and its clinical expression. Genomic DNA from 154 patients (74 men, 80 women; mean age, 53 years) with a diagnosis of DILI as assessed with the Council for International Organizations of Medical Science scale and 250 sex- and age-matched healthy controls were analyzed. A multiplex polymerase chain reaction-based method was used to detect GSTM1 and GSTT1 gene deletions. Carriers of double GSTT1-M1 null genotypes had a 2.70-fold increased risk of developing DILI compared with noncarriers (odds ratio 2.70, 95% confidence interval 1.45-5.03; P = 0.003). The odds ratio for DILI patients receiving antibacterials, and NSAIDs were 3.52 (P = 0.002), and 5.61 (P = 0.001), respectively. Patients with amoxicillin-clavulanate hepatotoxicity (n = 32) had a 2.81-fold increased risk (P = 0.037). Patients classified by the combined GSTT1 and GSTM1 null genotypes did not differ with regard to the type of injury, clinical presentation, or outcome, except for the predominance of women in the combined null genotype (P < 0.001). CONCLUSION: The double-null genotype for GSTT1 and GSTM1 might play a role in determining the susceptibility to develop DILI, as a general mechanism that occurs regardless of the type of drug involved, and predominantly in women. SN - 1527-3350 UR - https://www.unboundmedicine.com/medline/citation/18666253/Glutathione_S_transferase_m1_and_t1_null_genotypes_increase_susceptibility_to_idiosyncratic_drug_induced_liver_injury_ L2 - https://doi.org/10.1002/hep.22370 DB - PRIME DP - Unbound Medicine ER -