title: Metabolism of triethylenetetramine and 1,12-diamino-3,6,9-triazadodecane by the spermidine/spermine-N(1)-acetyltransferase and thialysine acetyltransferase.
abstract: 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-N(1)-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.
authors.affiliation: Department of Biotechnology and Molecular Medicine, A.I. Virtanen Institute, Finland.
authors.forename: Mervi T
authors.initials: MT
authors.lastname: Hyvönen
authors.forename: Janne
authors.initials: J
authors.lastname: Weisell
authors.forename: Alex R
authors.initials: AR
authors.lastname: Khomutov
authors.forename: Leena
authors.initials: L
authors.lastname: Alhonen
authors.forename: Jouko
authors.initials: J
authors.lastname: Vepsäläinen
authors.forename: Tuomo A
authors.initials: TA
authors.lastname: Keinänen
mesh_terms: D000123:Acetyltransferases / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D022781:Hepatocytes / Q000201:enzymology / Q000378:metabolism; D051379:Mice; D011994:Recombinant Proteins / Q000378:metabolism; D013096:Spermine / Q000031:analogs & derivatives* / Q000378:metabolism; D014266:Trientine / Q000378:metabolism*; D000099228:Diamine N-Acetyltransferase
chemical_list: D000123:Acetyltransferases; D011994:Recombinant Proteins; D013096:Spermine; D014266:Trientine; D000099228:Diamine N-Acetyltransferase; C502960:1,12-diamino-3,6,9-triazadodecane