Alterations of non-enzymatic biochemistry in uremia, diabetes, and atherosclerosis ("carbonyl stress").

Aging is accompanied by a progressive and irreversible non-enzymatic modification of protein by carbohydrates, eventually yielding the advanced glycation end products (AGEs). Age generation (Maillard reaction) is markedly augmented in diabetes with sustained hyperglycemia but also in normoglycemic uremia and atherosclerosis. Recent studies have brought new insights into broad derangements in non-enzymatic biochemistry involving not only carbohydrates but also lipids, present in diabetes, uremia, and atherosclerosis. The latter have in common increased levels of reactive carbonyl compounds (RCOs) with attendant protein modifications ("carbonyl stress"). Carbonyl stress might be derived from 1) hyperglycemia (lipemia), 2) oxidative stress, and/or 3) impaired detoxification of RCOs. Manipulation of carbonyl stress in diabetes, uremia and atherosclerosis opens new therapeutic approaches including redox modulation, RCO detoxification, and carbonyl stress inhibition. The first generation of carbonyl stress inhibitors such as aminoguanidine trap RCOs with its hydrazine group. Unfortunately, aminoguanidine (AG) traps pyridoxal as well as noxious RCOs, so that its long-term administration in animals results in vitamin B6 deficiency and neurotoxicity. Fortunately, newer compounds devoid of such side effects, have opened exciting prospects. Widely used hypotensive agents, such as angiotensin converting enzyme (ACE) inhibitor and angiotensin II receptor antagonist, but not calcium blockers, prove more effective than AG in attenuating the production of AGEs. Unlike AG, they do not act as RCO trapping agents, but impact upon the production of RCO precursors by scavenging a variety of radicals and altering oxidative stress, a mechanism similar to that involved in the inhibitory action of nitric oxide on AGE formation. These results provide a new framework to assess families of compounds according to their mechanisms of action.