Glutathione maintenance mitigates age-related susceptibility to redox cycling agents.
Glutathione maintenance mitigates age-related susceptibility to redox cycling agents.
复制标题
谷胱甘肽维持可缓解与年龄相关的氧化还原循环剂的敏感性。
DOI：
10.1016/j.redox.2016.09.010
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发表时间：
2016-12
期刊：
影响因子：
11.4
通讯作者：
Hagen, Tory M.
中科院分区：
文献类型：
--
作者：
Thomas, Nicholas O.;Shay, Kate P.;Kelley, Amanda R.;Butler, Judy A.;Hagen, Tory M.
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 (p<0.05 and p≤0.01 respectively; N=3). We therefore provided 400 µM N-acetyl-cysteine (NAC) to hepatocytes from old rats before menadione exposure to alleviate limits in cysteine substrate availability for GSH synthesis during challenge. NAC pretreatment resulted in a >2-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. 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.
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影响因子：
9.3
作者：
Gouix, Elsa;Buisson, Alain;Had-Aissouni, Laurence
通讯作者：
Had-Aissouni, Laurence
影响因子：
2.9
作者：
FREI, B;WINTERHALTER, KH;RICHTER, C
通讯作者：
RICHTER, C
DOI：
10.1016/s0167-4781(00)00238-4
发表时间：
2000-12-15
期刊：
BIOCHIMICA ET BIOPHYSICA ACTA-GENE STRUCTURE AND EXPRESSION
影响因子：
--
作者：
Chan, JY;Kwong, M
通讯作者：
Kwong, M
影响因子：
5.3
作者：
CORNET, M;MERTENS, K;ROGIERS, V
通讯作者：
ROGIERS, V
影响因子：
3.8
作者：
Chung, JH;Seo, DC;Seung, SA
通讯作者：
Seung, SA