Identification of α-dicarbonyl scavengers for cellular protection against carbonyl stress

摘要:

Tissue deterioration and aging have long been associated with the accumulation of chemically induced protein and DNA damage. Reactive oxygen species (ROS) and reactive carbonyl species (RCS), especially α-dicarbonyl compounds, are key mediators of damage caused by oxidative stress, glycation, and UV-irradiation. The toxic effects of ROS are counteracted in vivo by antioxidants and antioxidant enzymes, and the deleterious effects of one RCS, methylglyoxal, are counteracted by a ubiquitous glyoxalase system. Carbonyl stress as a result of toxic effects of various mono-dicarbonyls (e.g. 4-hydroxynonenal) and α-dicarbonyls (e.g. glyoxal and deoxyosones) cannot be directly antagonized by antioxidants, and only a small number of biological carbonyl scavengers like glutathione (GSH) have been identified to date. We have developed a new screening method for the identification of carbonyl scavengers using a rapid glycation system that proceeds independent of oxygen and therefore, excludes identification of inhibitory compounds acting as antioxidants. Using this screening assay adapted to 96-well microtiter plates, we have identified the cysteine derivative 3,3-dimethyl-d-cysteine as a potent inhibitor of non-oxidative advanced glycation. Comparative kinetic analyses demonstrated the superior α-oxoaldehyde-scavenging activity of d-penicillamine over that of aminoguanidine. d-Penicillamine traps α-oxoaldehydes by forming a 2-acylthiazolidine derivative as shown by structure elucidation of reaction products between d-penicillamine and methylglyoxal or phenylglyoxal. We demonstrated that upon co-incubation, d-penicillamine protects human skin keratinocytes and fibroblasts (CF3 cells) against glyoxal- and methylglyoxal-induced carbonyl toxicity. Our research qualifies α-amino-β-mercapto-β,β-dimethyl-ethane as a promising pharmacophore for the development of related α-dicarbonyl scavengers as therapeutic agents to protect cells against carbonyl stress.

展开

DOI:

10.1016/S0006-2952(01)00915-7

被引量:

174

年份:

2002

通过文献互助平台发起求助,成功后即可免费获取论文全文。

我们已与文献出版商建立了直接购买合作。

你可以通过身份认证进行实名认证,认证成功后本次下载的费用将由您所在的图书馆支付

您可以直接购买此文献,1~5分钟即可下载全文,部分资源由于网络原因可能需要更长时间,请您耐心等待哦~

身份认证 全文购买

相似文献

参考文献

引证文献

来源期刊

Biochemical Pharmacology
1 February 2002

研究点推荐

引用走势

2010
被引量:21

辅助模式

0

引用

文献可以批量引用啦~
欢迎点我试用!

引用