Glutathione maintenance mitigates age-related susceptibility to redox cycling agents

Autor: Kate Petersen Shay, Tory M. Hagen, J. A. Butler, Amanda Kelley, Nicholas O. Thomas
Rok vydání: 2016
Předmět:
Male
0301 basic medicine
Aging
MDA
Malonyldialdehyde
Clinical Biochemistry
Menadione
GPX4
Biochemistry
Lipid peroxidation
chemistry.chemical_compound
0302 clinical medicine
ARE
Antioxidant Response Element
NAD(P)H Dehydrogenase (Quinone)
NQO2
NAD(P)H:quinone oxido-reductase 2
GPX4
Glutathione Peroxidase 4
lcsh:QH301-705.5
lcsh:R5-920
Gene Expression Regulation
Developmental
Vitamin K 3
TRE
TPA-Response Element
Glutathione
3. Good health
RIPA
Radioimmunoprecipitation assay
Detoxification Capacity
030220 oncology & carcinogenesis
Toxicity
Menadione (PubChem CID: 4055)
lcsh:Medicine (General)
Oxidation-Reduction
Research Paper
medicine.medical_specialty
Redox-cycling
Nrf2
Nuclear factor (erythroid-derived 2)-like 2
NAC (PubChem CID: 12035)
03 medical and health sciences
BSO (PubChem CID: 119565)
Internal medicine
Detoxification
medicine
Animals
DCPIP
Dichlorophenolindophenol
BSO
Buthionine-S
R-Sulfoximine
LOO
Lipid peroxide
Glutathione Peroxidase
LDHA
Lactate dehydrogenase A
Organic Chemistry
Phospholipid Hydroperoxide Glutathione Peroxidase
DMF (PubChem CID: 6228)
Rats
Inbred F344
Acetylcysteine
Rats
030104 developmental biology
Endocrinology
lcsh:Biology (General)
chemistry
CPR
Cytochrome P450 reductase
Hepatocytes
NQO1
NAD(P)H:quinone oxido-reductase 1
Lipid Peroxidation
NAD+ kinase
Xenobiotic
Zdroj: Redox Biology
Redox Biology, Vol 10, Iss C, Pp 45-52 (2016)
ISSN: 2213-2317
DOI: 10.1016/j.redox.2016.09.010
Popis: Isolated hepatocytes from young (4–6 mo) and old (24–26 mo) F344 rats were exposed to increasing concentrations of menadione, a vitamin K derivative and redox cycling agent, to determine whether the age-related decline in Nrf2-mediated detoxification defenses resulted in heightened susceptibility to xenobiotic insult. An LC50 for each age group was established, which showed that aging resulted in a nearly 2-fold increase in susceptibility to menadione (LC50 for young: 405 μM; LC50 for old: 275 μM). Examination of the known Nrf2-regulated pathways associated with menadione detoxification revealed, surprisingly, that NAD(P)H: quinone oxido-reductase 1 (NQO1) protein levels and activity were induced 9-fold and 4-fold with age, respectively (p=0.0019 and p=0.018; N=3), but glutathione peroxidase 4 (GPX4) declined by 70% (p=0.0043; N=3). These results indicate toxicity may stem from vulnerability to lipid peroxidation instead of inadequate reduction of menadione semi-quinone. Lipid peroxidation was 2-fold higher, and GSH declined by a 3-fold greater margin in old versus young rat cells given 300 µM menadione (p2-fold reduction in cell death, suggesting that the age-related increase in menadione susceptibility likely stems from attenuated GSH-dependent defenses. This data identifies cellular targets for intervention in order to limit age-related toxicological insults to menadione and potentially other redox cycling compounds.
Graphical abstract fx1
Highlights • Menadione toxicity is nearly two-fold higher with age by LC50 in F344 hepatocytes. • Glutathione (GSH) loss during menadione treatment is accelerated with age. • Age-related loss of GPX4 protein correlates with increased menadione-induced MDA. • NAC maintained GSH mitigates age-related susceptibility to redox cycling menadione.
Databáze: OpenAIRE
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