RT Journal Article SR Electronic T1 Metabolism of Triethylenetetramine and 1,12-Diamino-3,6,9-Triazadodecane by the Spermidine/Spermine-N1-Acetyltransferase and Thialysine Acetyltransferase JF Drug Metabolism and Disposition JO Drug Metab Dispos FD American Society for Pharmacology and Experimental Therapeutics SP 30 OP 32 DO 10.1124/dmd.112.047274 VO 41 IS 1 A1 Hyvönen, Mervi T. A1 Weisell, Janne A1 Khomutov, Alex R. A1 Alhonen, Leena A1 Vepsäläinen, Jouko A1 Keinänen, Tuomo A. YR 2013 UL http://dmd.aspetjournals.org/content/41/1/30.abstract AB Triethylenetetramine (TETA; Syprine; Merck Rahway, NJ), a drug for Wilson’s disease, is a copper chelator and a charge-deficient analog of polyamine spermidine. We recently showed that TETA is metabolized in vitro by polyamine catabolic enzyme spermidine/spermine-N1-acetyltransferase (SSAT1) and by thialysine acetyltransferase (SSAT2) to its monoacetylated derivative (MAT). The acetylation of TETA is increased in SSAT1-overexpressing mice compared with wild-type mice. However, SSAT1-deficient mice metabolize TETA at the same rate as the wild-type mice, indicating the existence of another N-acetylase respons 2ible for its metabolism in mice. Here, we show that siRNA-mediated knockdown of SSAT2 in HEPG2 cells and in primary hepatocytes from the SSAT1-deficient or wild-type mice reduced the metabolism of TETA to MAT. By contrast, 1,12-diamino-3,6,9-triazadodecane(SpmTrien), a charge-deficient spermine analog, was an extremely poor substrate of human recombinant SSAT2 and was metabolized by SSAT1 in HEPG2 cells and in wild-type primary hepatocytes. Thus, despite the similar structures of TETA and SpmTrien, SSAT2 is the main acetylator of TETA, whereas SpmTrien is primarily acetylated by SSAT1.