The influence of catabolic reactions on polyamine excretion

Abstract

Complete inhibition of polyamine catabolism is possible by combined administration of two compounds. Aminoguanidine (25 mg/kg body wt., intraperitoneally) inhibits all reactions that are catalysed by copper-containing amine oxidases (CuAO). The products of the CuAO-catalysed reactions cannot be reconverted into polyamines (terminal catabolism) and therefore usually escape observation. N1-Methyl-N2-(buta-2,3-dienyl)butane-1,4-diamine (MDL 72521) is a new inhibitor of polyamine oxidase. It inhibits completely the degradation of N1-acetylspermidine and N1-acetylspermine. The enhanced excretion of N1-acetylspermidine in urine after administration of 20 mg of MDL 72521/day per kg body wt. is a measure of the rate of spermidine degradation in vivo to putrescine, and thus of the quantitative significance of the interconversion pathway. From the enhancement of total polyamine excretion by aminoguanidine-treated rats, one can calculate that only about 40% of the polyamines that are destined for elimination are usually observed in the urine, the other 60% being catabolized along the CuAO-catalysed pathways. The normally observed urinary polyamine pattern gives, therefore, an unsatisfactory picture of the actual polyamine elimination. Although aminoguanidine alone is sufficient to block terminal polyamine catabolism, rats that were treated with a combination of aminoguanidine and MDL 72521 excrete more polyamines than those that received aminoguanidine alone. The reason is that a certain proportion of putrescine, which is formed by degradation of spermidine, is normally reutilized for polyamine biosynthesis. In MDL 72521-treated animals this proportion appears in the urine in the form of N1-acetylspermidine. Thus it is possible to determine polyamine interconversion and re-utilization in vivo and to establish a polyamine balance in intact rats by using specific inhibitors of the CuAO and of polyamine oxidase.