It was found that two inhibitors currently being used to inhibit spermidine formation in mammalian cells were more potent inhibitors of diamine oxidase than of polyamine synthesis. Eukaryotic S-adenosylmethionine decarboxylase is inhibited reversibly by 1,1'-[(methylethanediylidene)-dinitrilo]-diguanidine (MGBG) and irreversibly by 1,1'-[(methylethanediylidene)-dinitrilo]-bis-(3-aminoguanidine) (MBAG). Since this enzyme is essential for the generation of propylamine groups needed to convert putrescine into spermidine, these drugs were used to prevent spermidine synthesis in mammalian cells. It was found that both drugs were potent inhibitors in vitro of pig kidney diamine oxidase activity. MGBG appeared to be a non-competitive inhibitor with a Ki of about 0.1 μM and MBAG was a competitive inhibitor with a Ki of 0.02 μM. Inhibition by MBAG was partially reversible after prolonged dialysis. The period during which diaminc oxidasc activity remained suppressed in the rat after treatment with these inhibitors was determined by measuring the conversion of (1.414C] putrescine to 14CO2. A single dose of MGBG (60 mg/kg body wt) inhibited 14CO2production more than 90 per cent for 21 hr and a single dose of MBAG (50 mg/kg body wt) produced a similar inhibition for 72 hr.
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