mofegiline and methylamine

Semicarbazide-sensitive amine oxidase has been recognised to be a potential risk factor in vascular disorders associated with diabetic complications and to be related to mortality in patients suffering from heart disease. This enzyme, associated with the vascular system, catalyses the deamination of methylamine and aminoacetone, and also acts as an adhesion molecule related to leucocyte trafficking and inflammation. The deaminated products include the toxic aldehydes, formaldehyde and methylglyoxal, respectively, hydrogen peroxide and ammonia.. In this study, the KKAy mouse, a strain possessing features closely resembling those of Type II (non-insulin-dependent) diabetes mellitus has been used to substantiate the hypothesis. Vascular lesions were induced via chronic feeding of a high cholesterol diet.. Both MDL-72974A, a selective mechanism-based semicarbazide-sensitive amine oxidase inhibitor and aminoguanidine effectively inhibited aorta semicarbazide-sensitive amine oxidase activity, and caused a substantial increase in urinary methylamine, and a decrease in formaldehyde and methylgloxal levels. Inhibition of semicarbazide-sensitive amine oxidase also reduced oxidative stress, as shown by a reduction of malondialdehyde excretion. Both MDL-72974A and aminoguanidine reduced albuminuria, proteinuria and the number of atherosclerotic lesions in animals fed with a cholesterol diet over a period of treatment for 16 weeks.. Increased semicarbazide-sensitive amine oxidase-mediated deamination could be involved in the cascade of atherogenesis related to diabetic complications.

Topics: Albuminuria; Allyl Compounds; Amine Oxidase (Copper-Containing); Amines; Animals; Arteriosclerosis; Butylamines; Cholesterol, Dietary; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Diet, Atherogenic; Disease Models, Animal; Enzyme Inhibitors; Female; Guanidines; Methylamines; Mice; Mice, Inbred Strains

Methylamine is a constituent of cigarette smoke and the major end product of nicotine metabolism. Smoking or nicotine can induce the release of adrenaline, which is in turn deaminated by monoamine oxidase, also producing methylamine. We found that the urinary level of methylamine was significantly elevated following administration of nicotine (25 mg/Kg, i.p.). Semicarbazide-sensitive amine oxidase (SSAO) inhibitors further increased the excretion of methylamine induced by nicotine. Following administration of L-(-)-[N-methyl-3H]nicotine long-lasting irreversible radioactive adducts were detected in different mouse tissues and such adduct formation could be blocked by selective SSAO inhibitors. These adducts are probably cross-linked oligoprotein complexes cross-linked by formaldehyde. The findings support the idea that nicotine can enhance SSAO/methylamine-mediated increase of formaldehyde and oxidative stress and this could in part contribute the adverse effect of health associated with smoking.

Topics: Allyl Compounds; Amine Oxidase (Copper-Containing); Animals; Biotransformation; Butylamines; Enzyme Inhibitors; Formaldehyde; Male; Methylamines; Mice; Nicotine; Rats; Rats, Wistar; Smoking; Tissue Distribution; Tritium

The mouse is known to be highly resistant to atherosclerosis. However, some inbred mouse strains are vulnerable to atherosclerosis when they are fed a high-cholesterol, high-fat diet. Increased deamination of methylamine (MA) and the subsequent production of formaldehyde has been recently shown to be a potential risk factor of atherosclerosis. In the present study semicarbazide-sensitive amine oxidase (SSAO)-mediated MA turnover in C57BL/6 mouse, a strain very susceptible to atherosclerosis, has been assessed in comparison to a moderate, i.e. BALB/c, and resistant, i.e. CD1, mouse strains. Kidney and aorta SSAO activities were found to be significantly increased in C57BL/6 in comparison to BALB/c and CD1 mice. A significant increase of urinary MA and formaldehyde were detected in C57BL/6. [14C]MA following intravenous injection would be quickly metabolized by SSAO. The labeled formaldehyde product would cross link with proteins. C57BL/6 exhibits significantly higher labeled protein adducts than BALB/c and CD1 in response to [14C]MA. The results indicated that mice vulnerable to atherosclerosis possess an increased SSAO-mediated MA turnover. The increase of production of formaldehyde, possibly other aldehydes, may induce endothelial injury or be chronically involved in protein cross-linking and subsequent angiopathy.

Topics: Allyl Compounds; Amine Oxidase (Copper-Containing); Animals; Aorta; Arteriosclerosis; Butylamines; Chromatography, High Pressure Liquid; Diet, Atherogenic; Disease Susceptibility; Enzyme Inhibitors; Formaldehyde; Guanidines; Kidney; Male; Methylamines; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Risk Factors

Methylamine can be converted by semicarbazide-sensitive amine oxidase (SSAO) to formaldehyde and hydrogen peroxide, which have been proven to be toxic towards cultured endothelial cells. We investigated whether or not these deaminated products from methylamine can exert potentially hazardous toxic effects in vivo. Long lasting residual radioactivity in different tissues was detected following administration of [14C]-methylamine in the mouse. Approximately 10% of the total administered radioactivity could even be detected 5 days after injection of [14C]-methylamine. Eighty percent of the formation of irreversible adducts can be blocked by a highly selective SSAO inhibitor, (E)-2-(4-fluorophenethyl)-3-fluoroallylamine hydrochloride (MDL-72974A). The residual radioactivity was primarily associated with the insoluble tissue components and the soluble macromolecules. Radioactively labelled macromolecules were fragmented following enzymatic proteolysis. Results suggest that the formaldehyde derived from methylamine interacts with proteins in vivo. In the streptozotocin-induced diabetic mice, both SSAO activity and the formation of residual radioactivity were found to be significantly increased in the kidney. Chronic administration of methylamine enhances blood prorenin level, which strongly suggests that uncontrolled deamination of methylamine may be a risk factor for initiation of endothelial injury, and subsequent genesis of atherosclerosis.

Topics: Allyl Compounds; Amine Oxidase (Copper-Containing); Animals; Butylamines; Deamination; Diabetes Mellitus, Experimental; Endothelium, Vascular; Enzyme Inhibitors; Enzyme Precursors; Formaldehyde; Hydrogen Peroxide; Kidney; Male; Methylamines; Mice; Renin; Risk Factors; Streptozocin