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 reduces the development of atherosclerotic plaques and prevents experimental diabetic nephropathy. We have found that aminoguanidine is also quite potent at inhibiting semicarbazide-sensitive amine oxidase (SSAO) both 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, respectively. Serum SSAO activity was reported to be increased in diabetic patients and positively correlated with the amount of plasma glycated haemoglobin. Increased SSAO has also been demonstrated in diabetic animal 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 streptozotocin (STZ)-induced diabetic rats following administration of aminoguanidine. The non-hydrazine SSAO inhibitor (E)-2-(4-fluorophenethyl)-3-fluoroallylamine hydrochloride (MDL-72974A) has been shown to reduce urinary excretion of lactate dehydrogenase (an indicator of nephropathy) in STZ-induced diabetic rats. Formaldehyde not only induces protein crosslinking, but also enhances the advanced glycation of proteins in vitro. 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 implications for the use of aminoguanidine to prevent glycoxidation have been discussed.
Yu
P H
PH
Department of Psychiatry, University of Saskatchewan, Saskatoon, Canada.
Zuo
D M
DM
D006631:Amine Oxidase (Copper-Containing) / Q000032:analysis / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D001011:Aorta / Q000737:chemistry / Q000201:enzymology; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005557:Formaldehyde / Q000494:pharmacology; D017127:Glycation End Products, Advanced / Q000378:metabolism; D006146:Guanidines / Q000494:pharmacology*; D006801:Humans; D007668:Kidney / Q000201:enzymology; D007770:L-Lactate Dehydrogenase / Q000652:urine; D008744:Methylamines / Q000652:urine; D051381:Rats; D017208:Rats, Wistar; D012260:Ribonucleases / Q000187:drug effects / Q000378:metabolism; D013997:Time Factors; D014469:Umbilical Arteries / Q000737:chemistry
D004791:Enzyme Inhibitors; D017127:Glycation End Products, Advanced; D006146:Guanidines; D008744:Methylamines; D005557:Formaldehyde; C027451:methylamine; D007770:L-Lactate Dehydrogenase; D006631:Amine Oxidase (Copper-Containing); D012260:Ribonucleases; C004479:pimagedine