PT - JOURNAL ARTICLE AU - Marc Cerrada-Gimenez AU - Janne Weisell AU - Mervi T. Hyvönen AU - Myung Hee Park AU - Leena Alhonen AU - Jouko Vepsäläinen AU - Tuomo A. Keinänen TI - Complex N<em>-</em>Acetylation of Triethylenetetramine AID - 10.1124/dmd.111.041798 DP - 2011 Dec 01 TA - Drug Metabolism and Disposition PG - 2242--2249 VI - 39 IP - 12 4099 - http://dmd.aspetjournals.org/content/39/12/2242.short 4100 - http://dmd.aspetjournals.org/content/39/12/2242.full SO - Drug Metab Dispos2011 Dec 01; 39 AB - Triethylenetetramine (TETA) is an efficient copper chelator that has versatile clinical potential. We have recently shown that spermidine/spermine-N1-acetyltransferase (SSAT1), the key polyamine catabolic enzyme, acetylates TETA in vitro. Here, we studied the metabolism of TETA in three different mouse lines: syngenic, SSAT1-overexpressing, and SSAT1-deficient (SSAT1-KO) mice. The mice were sacrificed at 1, 2, or 4 h after TETA injection (300 mg/kg i.p.). We found only N1-acetyltriethylenetetramine (N1AcTETA) and/or TETA in the liver, kidney, and plasma samples. As expected, SSAT1-overexpressing mice acetylated TETA at an accelerated rate compared with syngenic and SSAT1-KO mice. It is noteworthy that SSAT1-KO mice metabolized TETA as syngenic mice did, probably by thialysine acetyltransferase, which had a Km value of 2.5 ± 0.3 mM and a kcat value of 1.3 s−1 for TETA when tested in vitro with the human recombinant enzyme. Thus, the present results suggest that there are at least two N-acetylases potentially metabolizing TETA. However, their physiological significance for TETA acetylation requires further studies. Furthermore, we detected chemical intramolecular N-acetyl migration from the N1 to N3 position of N1AcTETA and N1,N8-diacetyltriethylenetetramine in an acidified high-performance liquid chromatography sample matrix. The complex metabolism of TETA together with the intramolecular N-acetyl migration may explain the huge individual variations in the acetylation rate of TETA reported earlier.