Limitation of adipose tissue enlargement in rats chronically treated with semicarbazide-sensitive amine oxidase and monoamine oxidase inhibitors.. C Carpéné; V Abello; Z Iffiú-Soltész; N Mercier; Bruno Fève; P Valet (2008) Pharmacological research : the official journal of the Italian Pharmacological Society display abstract
Inhibition of semicarbazide-sensitive amine oxidases (SSAO) and monoamine oxidases (MAO) reduces fat deposition in obese rodents: chronic administration of the SSAO-inhibitor semicarbazide (S) in combination with pargyline (MAO-inhibitor) has been shown to reduce body weight gain in obese Zucker rats, while (E)-2-(4-fluorophenethyl)-3-fluoroallylamine, an SSAO- and MAO-B inhibitor, has been reported to limit weight gain in obese and diabetic mice. Our aim was to state whether such weight gain limitation could occur in non-obese, non-diabetic rats and to extend these observations to other amine oxidase inhibitors. Prolonged treatment of non-obese rats with a high dose of S (900 micromol kg(-1) day(-1)) reduced body weight gain and limited white adipose tissue enlargement. When chronically administered at a threefold lower dose, S also inhibited SSAO activity but not fat depot enlargement, suggesting that effects other than SSAO inhibition were involved in adipose tissue growth retardation. However, combined treatment of this lower dose of S with pargyline inhibited SSAO, MAO, energy intake, weight gain and fat deposition. Adipocytes from treated rats exhibited unchanged insulin responsiveness but impaired antilipolytic responses to amine oxidase substrates. Phenelzine clearly inhibited both MAO and SSAO when tested on adipocytes. Obese rats receiving phenelzine i.p. at 17 micromol kg(-1) day(-1) for 3 weeks, exhibited blunted MAO and SSAO activities in any tested tissue, diminished body weight gain and reduced intra-abdominal adipose tissue. Their adipocytes were less responsive to lipogenesis activation by tyramine or benzylamine. These observations suggest that SSAO inhibition is not sufficient to impair fat deposition. However, combined MAO and SSAO inhibition limits adiposity in non-obese as well as in obese rats.
Inhibition of bovine lung semicarbazide-sensitive amine oxidase (SSAO) by some hydrazine derivatives.. J M Lizcano; A Fernández de Arriba; K F Tipton; M Unzeta (1996) Biochemical pharmacology display abstract
Microsomal semicarbazide-sensitive amine oxidase (SSAO) from bovine lung was shown to be inhibited by a number of hydrazine derivatives, but the mechanisms of inhibition were found to differ. Hydralazine behaved as an irreversible and partially time-dependent inhibitor with an IC50 value of 1 microM under the conditions used. Phenylhydrazine was found to be a potent irreversible inhibitor of SSAO (IC50 30 nM). Semicarbazide behaved as a specific irreversible inhibitor (active-site-directed irreversible inhibitor) in first forming a non-covalent enzyme-semicarbazide complex (with a Ki value of 85 microM), which then reacted to give an irreversibly inhibited enzyme species in a reaction defined by the first-order rate constant k2 = 0.065 min-1. Phenelzine behaved as a reversible inhibitor, but dialysis at 37 degrees C was found to be necessary to obtain full recovery of enzyme activity. The dependence of inhibition on phenelzine concentration was complex and consistent with multiple binding sites for this inhibitor. This diversity in the action of a family of compounds with the same functional group must be taken into account in attempts to design more specific inhibitors of this enzyme.