AMINOGUANIDINE INHIBITS SEMICARBAZIDE-SENSITIVE AMINE OXIDASE ACTIVITY - IMPLICATIONS FOR ADVANCED GLYCATION AND DIABETIC COMPLICATIONS

Aminoguanidine, a nucleophilic hydrazine, has been shown to be capable of blocking the formation of advanced glycation end products. It redu ces the development of atherosclerotic plaques and prevents experiment al diabetic nephropathy. We have found that aminoguanidine is also qui te potent at inhibiting semicarbazide-sensitive amine oxidase (SSAO) b oth in vitro and in vivo. The inhibition is irreversible. This enzyme catalyses the deamination of methylamine and aminoacetone, which leads to the production of cytotoxic formaldehyde and methylglyoxal, respec tively. Serum SSAO activity was reported to be increased in diabetic p atients and positively correlated with the amount of plasma glycated h aemoglobin. Increased SSAO has also been demonstrated in diabetic anim al models. Urinary excretion of methylamine is substantially increased in the rats following acute or chronic treatment with aminoguanidine. Urinary methylamine levels were substantially increased in streptozot ocin (STZ)-induced diabetic rats following administration of aminoguan idine. The non-hydrazine SSAO inhibitor (E)-2-(4-fluoro-phenethyl)-3-f luoroallylamine hydrochloride (MDL-72974A) has been shown to reduce ur inary excretion of lactate dehydrogenase (an indicator of nephropathy) in STZ-induced diabetic rats. Formaldehyde not only induces protein c rosslinking, but also enhances the advanced glycation of proteins in v itro. The results support the hypothesis that increased SSAO-mediated deamination may be involved in structural modification of proteins and contribute to advanced glycation in diabetes. The clinical implicatio ns for the use of aminoguanidine to prevent glycoxidation have been di scussed.