TY - JOUR T1 - Metabolism of Triethylenetetramine (TETA) and 1,12-diamino-3,6,9-triazadodecane (SpmTrien) by the Spermidine/spermine-N<sup>1</sup>-acetyltransferase and Thialysine Acetyltransferase JF - Drug Metabolism and Disposition JO - Drug Metab Dispos DO - 10.1124/dmd.112.047274 SP - dmd.112.047274 AU - Mervi T Hyvonen AU - Janne Weisell AU - Alex Khomutov AU - Leena Alhonen AU - Jouko Vepsalainen AU - Tuomo A Keinanen Y1 - 2012/01/01 UR - http://dmd.aspetjournals.org/content/early/2012/09/28/dmd.112.047274.abstract N2 - Triethylenetetramine (TETA), 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 as compared to 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 responsible 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. ER -