Deficiency of Glutathione Transferase Zeta Causes Oxidative Stress and Activation of Antioxidant Response Pathways
| العنوان: | Deficiency of Glutathione Transferase Zeta Causes Oxidative Stress and Activation of Antioxidant Response Pathways |
|---|---|
| المؤلفون: | John D. Hayes, Cindy E.L. Lim, Anneke C. Blackburn, M. W. Anders, Philip G. Board, Klaus I. Matthaei, Matthew C. Taylor, Jean Cappello |
| المصدر: | Molecular Pharmacology. 69:650-657 |
| بيانات النشر: | American Society for Pharmacology & Experimental Therapeutics (ASPET), 2005. |
| سنة النشر: | 2005 |
| مصطلحات موضوعية: | Male, medicine.medical_specialty, Antioxidant, medicine.medical_treatment, Glutathione reductase, GSTZ1, medicine.disease_cause, Antioxidants, Xenobiotics, Mice, chemistry.chemical_compound, Internal medicine, medicine, Animals, Antioxidant Response Elements, Acetaminophen, Glutathione Transferase, Pharmacology, Chemistry, Catabolism, Metabolism, Glutathione, Mice, Mutant Strains, Isoenzymes, Oxidative Stress, Endocrinology, Liver, Biochemistry, Molecular Medicine, Female, Oxidative stress |
| الوصف: | Glutathione S-transferase (GST) zeta (GSTZ1-1) plays a significant role in the catabolism of phenylalanine and tyrosine, and a deficiency of GSTZ1-1 results in the accumulation of maleylacetoacetate and its derivatives maleylacetone (MA) and succinylacetone. Induction of GST subunits was detected in the liver of Gstz1(-/-) mice by Western blotting with specific antisera and high-performance liquid chromatography analysis of glutathione affinity column-purified proteins. The greatest induction was observed in members of the mu class. Induction of NAD(P)H:quinone oxidoreductase 1 and the catalytic and modifier subunits of glutamate-cysteine ligase was also observed. Many of the enzymes that are induced in Gstz1(-/-) mice are regulated by antioxidant response elements that respond to oxidative stress via the Keap1/Nrf2 pathway. It is significant that diminished glutathione concentrations were also observed in the liver of Gstz1(-/-) mice, which supports the conclusion that under normal dietary conditions, the accumulation of electrophilic intermediates such as maleylacetoacetate and MA results in a high level of oxidative stress. Elevated GST activities in the livers of Gstz1(-/-) mice suggest that GSTZ1-1 deficiency may alter the metabolism of some drugs and xenobiotics. Gstz1(-/-) mice given acetaminophen demonstrated increased hepatotoxicity compared with wild-type mice. This toxicity may be attributed to the increased GST activity or the decreased hepatic concentrations of glutathione, or both. Patients with acquired deficiency of GSTZ1-1 caused by therapeutic exposure to dichloroacetic acid for the clinical treatment of lactic acidosis may be at increased risk of drug- and chemical-induced toxicity. |
| تدمد: | 1521-0111 0026-895X |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::4023b345ddb623a9306854519f691221 https://doi.org/10.1124/mol.105.018911 |
| رقم الأكسشن: | edsair.doi.dedup.....4023b345ddb623a9306854519f691221 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15210111 0026895X |
|---|