RT Journal Article
SR Electronic
T1 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
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.