Biol. Pharm. Bull. 28(4) 569—573 (2005)

mine (spm), present in mammalian tissues, are regulated under a variety of physiological conditions. Their tissue concentrations are controlled by a number of factors: (1) polyamine biosynthetic enzymes, such as ornithine decarboxylase (ODC), S-adenosyl-L-methionine decarboxylase (AdoMetDC), spermidine synthase (spd-syn) and spermine synthase (spm-syn); (2) polyamine catabolic enzymes, such as spd/spm N-acetyltransferase (SSAT), polyamine oxidase (PAO), spermine oxidase (SMO) and diamine oxidase (DAO); and (3) the polyamine transport system on the cell membrane. The polyamines metabolic pathways catalyzed by these enzymes have been previously established; however, it is unclear how these factors function in vivo to regulate each polyamine under specific physiological conditions. A variety of inhibitors of these enzymes have been used, not only to elucidate the physiological significance of polyamines, but also to regulate cell growth, as polyamines are involved, either directly or indirectly, in many cellular events through their interactions with macromolecules and other cellular components. In liver regeneration, when cells are growing actively, putrescine and spd levels remain high, and the spm level is lower; this trend is reversed when cell growth is arrested. This suggests that downregulation of spd concentration concomitant with spm upregulation, might be associated with a reduced cell growth rate. In cultured cells, inhibition of spd-syn led to a decrease of spd and an increase of spm, but in short-term experiments, using the inhibitors, S-adenosyl-1,8-diamino-3-thiooctane (AdoDato) and trans-4-methylcyclohexylamine (4MCHA), little or no change in growth was observed. We obtained similar results in a study using rats administered 4MCHA, dissolved in drinking water and available ad libitum, for a period of 10 d. The basic response of cells treated with spdsyn inhibitors was elucidated from these studies. However, no detailed quantitative study has been performed in vivo on the effect of spd-syn inhibitors, although some studies have used cyclohexylamine, which is an order of magnitude weaker than 4MCHA. Recently, we discovered a new inhibitor, 5-amino-1-pentene (APE), which showed a similar IC50 value to that of 4MCHA against purified spd-syn from rat prostate. The present work investigated spd downregulation and spm upregulation in rat tissues during continuous oral administration of 4MCHA over a 1-week or 1-month period. We predicted that normal physiological conditions would be disturbed if the manipulated polyamine contents were maintained in the rat tissues.