PT  - JOURNAL ARTICLE
AU  - Mervi T. Hyvönen
AU  - Janne Weisell
AU  - Alex R. Khomutov
AU  - Leena Alhonen
AU  - Jouko Vepsäläinen
AU  - Tuomo A. Keinänen
TI  - Metabolism of Triethylenetetramine and 1,12-Diamino-3,6,9-Triazadodecane by the Spermidine/Spermine-<em>N</em><sup>1</sup>-Acetyltransferase and Thialysine Acetyltransferase
AID  - 10.1124/dmd.112.047274
DP  - 2013 Jan 01
TA  - Drug Metabolism and Disposition
PG  - 30--32
VI  - 41
IP  - 1
4099  - http://dmd.aspetjournals.org/content/41/1/30.short
4100  - http://dmd.aspetjournals.org/content/41/1/30.full
SO  - Drug Metab Dispos2013 Jan 01; 41
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.