Chelation: A Fundamental Mechanism of Action of AGE Inhibitors, AGE Breakers, and Other Inhibitors of Diabetes Complications
Advanced glycation or glycoxidation end-products (AGE) increase in tissue proteins with age, and their rate of accumulation is increased in diabetes, nephropathy and inflammatory diseases. AGE inhibitors include a range of compounds that are proposed to act by trapping carbonyl and dicarbonyl intermediates in AGE formation. However, some among the newer generation of AGE inhibitors lack reactive functional groups that would trap reaction intermediates, indicating an alternative mechanism of action. We propose that AGE inhibitors function primarily as chelators, inhibiting metal-catalyzed oxidation reactions. The AGE-inhibitory activity of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers is also consistent with their chelating activity. Finally, compounds described as AGE breakers, or their hydrolysis products, also have strong chelating activity, suggesting that these compounds also act through their chelating activity. We conclude that chelation is the common, and perhaps the primary, mechanism of action of AGE inhibitors and breakers, and that chronic, mild chelation therapy should prove useful in treatment of diabetes and age-related diseases characterized by oxidative stress, inflammation and increased chemical modification of tissue proteins by advanced glycoxidation and lipoxidation end-products.
- Research Organization:
- Pacific Northwest National Lab. (PNNL), Richland, WA (United States). Environmental Molecular Sciences Lab. (EMSL)
- Sponsoring Organization:
- USDOE
- DOE Contract Number:
- AC05-76RL01830
- OSTI ID:
- 1036068
- Report Number(s):
- PNNL-SA-77027; DIAEAZ; 16303a; 400412000; TRN: US201205%%585
- Journal Information:
- Diabetes, Vol. 61, Issue 3; ISSN 0012-1797
- Country of Publication:
- United States
- Language:
- English
Similar Records
Nifedipine inhibits advanced glycation end products (AGEs) and their receptor (RAGE) interaction-mediated proximal tubular cell injury via peroxisome proliferator-activated receptor-gamma activation
A new indanedione derivative alleviates symptoms of diabetes by modulating RAGE-NF-kappaB pathway in db/db mice
Related Subjects
60 APPLIED LIFE SCIENCES
ANGIOTENSIN
CARBONYLS
DISEASES
ENZYME INHIBITORS
FUNCTIONALS
HYDROLYSIS
INFLAMMATION
MODIFICATIONS
OXIDATION
PROTEINS
REACTION INTERMEDIATES
THERAPY
TRAPPING
advanced glycation end-product (AGE)
AGE breaker
chelation
metal-catalyzed oxidation
oxidative stress
Environmental Molecular Sciences Laboratory