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Rapid CommunicationShort Communication

Metabolism of Triethylenetetramine and 1,12-Diamino-3,6,9-Triazadodecane by the Spermidine/Spermine-N1-Acetyltransferase and Thialysine Acetyltransferase

Mervi T. Hyvönen, Janne Weisell, Alex R. Khomutov, Leena Alhonen, Jouko Vepsäläinen and Tuomo A. Keinänen
Drug Metabolism and Disposition January 2013, 41 (1) 30-32; DOI: https://doi.org/10.1124/dmd.112.047274
Mervi T. Hyvönen
Department of Biotechnology and Molecular Medicine, A.I. Virtanen Institute (M.T.H., L.A.), School of Pharmacy (J.W., J.V., T.A.K.), Biocenter Kuopio, University of Eastern Finland, Kuopio Campus, Finland; and Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia (A.K.)
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Janne Weisell
Department of Biotechnology and Molecular Medicine, A.I. Virtanen Institute (M.T.H., L.A.), School of Pharmacy (J.W., J.V., T.A.K.), Biocenter Kuopio, University of Eastern Finland, Kuopio Campus, Finland; and Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia (A.K.)
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Alex R. Khomutov
Department of Biotechnology and Molecular Medicine, A.I. Virtanen Institute (M.T.H., L.A.), School of Pharmacy (J.W., J.V., T.A.K.), Biocenter Kuopio, University of Eastern Finland, Kuopio Campus, Finland; and Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia (A.K.)
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Leena Alhonen
Department of Biotechnology and Molecular Medicine, A.I. Virtanen Institute (M.T.H., L.A.), School of Pharmacy (J.W., J.V., T.A.K.), Biocenter Kuopio, University of Eastern Finland, Kuopio Campus, Finland; and Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia (A.K.)
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Jouko Vepsäläinen
Department of Biotechnology and Molecular Medicine, A.I. Virtanen Institute (M.T.H., L.A.), School of Pharmacy (J.W., J.V., T.A.K.), Biocenter Kuopio, University of Eastern Finland, Kuopio Campus, Finland; and Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia (A.K.)
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Tuomo A. Keinänen
Department of Biotechnology and Molecular Medicine, A.I. Virtanen Institute (M.T.H., L.A.), School of Pharmacy (J.W., J.V., T.A.K.), Biocenter Kuopio, University of Eastern Finland, Kuopio Campus, Finland; and Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia (A.K.)
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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-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.

Footnotes

  • ↵Embedded ImageThis article has supplemental material available at dmd.aspetjournals.org.

  • The research was supported by grants from the Academy of Finland, the Orion-Farmos Research Foundation, the Paulo Foundation, the strategic funding from the University of Eastern Finland, the Program of Molecular and Cell Biology of the Presidium of Russian Academy of Sciences, and the Russian Foundation for Basic Research [Grant #12-04-01487].

  • dx.doi.org/10.1124/dmd.112.047274.

  • Received June 12, 2012.
  • Accepted September 28, 2012.
  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 41 (1)
Drug Metabolism and Disposition
Vol. 41, Issue 1
1 Jan 2013
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Rapid CommunicationShort Communication

Metabolism of TETA and SpmTrien by SSAT1 and SSAT2

Mervi T. Hyvönen, Janne Weisell, Alex R. Khomutov, Leena Alhonen, Jouko Vepsäläinen and Tuomo A. Keinänen
Drug Metabolism and Disposition January 1, 2013, 41 (1) 30-32; DOI: https://doi.org/10.1124/dmd.112.047274

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Rapid CommunicationShort Communication

Metabolism of TETA and SpmTrien by SSAT1 and SSAT2

Mervi T. Hyvönen, Janne Weisell, Alex R. Khomutov, Leena Alhonen, Jouko Vepsäläinen and Tuomo A. Keinänen
Drug Metabolism and Disposition January 1, 2013, 41 (1) 30-32; DOI: https://doi.org/10.1124/dmd.112.047274
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