Metabolism of triethylenetetramine and 1,12-diamino-3,6,9-triazadodecane by the spermidine/spermine-N(1)-acetyltransferase and thialysine acetyltransferase.
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.
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TETA spermidine spermine Syprine thialysine TETA TETA TETA 1,12-diamino-3,6,9-triazadodecane SpmTrien Triethylenetetramine spermine copper thialysine triethylenetetramine 1,12-diamino-3,6,9-triazadodecane spermidine spermine SSAT1 SSAT2 SSAT1 TETA spermidine/spermine-N(1)-acetyltransferase SSAT1 thialysine acetyltransferase SSAT2 SSAT1 SSAT1 N-acetylase SSAT2 SSAT1 human recombinant SSAT2 SpmTrien thialysine acetyltransferase spermidine/spermine-N(1)-acetyltransferase TETA SpmTrien polyamine spermidine TETA polyamine