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Research ArticleArticle

Complex N-Acetylation of Triethylenetetramine

Marc Cerrada-Gimenez, Janne Weisell, Mervi T. Hyvönen, Myung Hee Park, Leena Alhonen, Jouko Vepsäläinen and Tuomo A. Keinänen
Drug Metabolism and Disposition December 2011, 39 (12) 2242-2249; DOI: https://doi.org/10.1124/dmd.111.041798
Marc Cerrada-Gimenez
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Janne Weisell
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Mervi T. Hyvönen
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Myung Hee Park
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Leena Alhonen
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Jouko Vepsäläinen
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Tuomo A. Keinänen
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Abstract

Triethylenetetramine (TETA) is an efficient copper chelator that has versatile clinical potential. We have recently shown that spermidine/spermine-N1-acetyltransferase (SSAT1), the key polyamine catabolic enzyme, acetylates TETA in vitro. Here, we studied the metabolism of TETA in three different mouse lines: syngenic, SSAT1-overexpressing, and SSAT1-deficient (SSAT1-KO) mice. The mice were sacrificed at 1, 2, or 4 h after TETA injection (300 mg/kg i.p.). We found only N1-acetyltriethylenetetramine (N1AcTETA) and/or TETA in the liver, kidney, and plasma samples. As expected, SSAT1-overexpressing mice acetylated TETA at an accelerated rate compared with syngenic and SSAT1-KO mice. It is noteworthy that SSAT1-KO mice metabolized TETA as syngenic mice did, probably by thialysine acetyltransferase, which had a Km value of 2.5 ± 0.3 mM and a kcat value of 1.3 s−1 for TETA when tested in vitro with the human recombinant enzyme. Thus, the present results suggest that there are at least two N-acetylases potentially metabolizing TETA. However, their physiological significance for TETA acetylation requires further studies. Furthermore, we detected chemical intramolecular N-acetyl migration from the N1 to N3 position of N1AcTETA and N1,N8-diacetyltriethylenetetramine in an acidified high-performance liquid chromatography sample matrix. The complex metabolism of TETA together with the intramolecular N-acetyl migration may explain the huge individual variations in the acetylation rate of TETA reported earlier.

Footnotes

  • This work was supported in part by grants from the Intramural Research Program of the National Institutes of Health National Institute of Dental and Craniofacial Research; the Academy of Finland; the North Savo Regional Fund of the Finnish Cultural Foundation; and the University of Eastern Finland strategic funding.

  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

    doi:10.1124/dmd.111.041798.

  • ↵Embedded Image The online version of this article (available at http://dmd.aspetjournals.org) contains supplemental material.

  • ABBREVIATIONS:

    TETA
    triethylenetetramine (1,8-diamino-3,6-diazaoctane)
    HFBA
    heptafluorobutyric acid
    N1AcTETA
    N1-monoacetyltriethylenetetramine
    N3AcTETA
    N3-monoacetyltriethylenetetramine
    N1N8DiAcTETA
    N1,N8-diacetyltriethylenetetramine
    PBS
    phosphate-buffered saline
    Spd
    spermidine
    Spm
    spermine
    SSA
    sulfosalisylic acid
    SSAT1
    spermidine/spermine N1-acetyltransferase
    hSSAT1
    human spermidine/spermine N1-acetyltransferase
    SSAT2
    thialysine acetyltransferase
    SSAT1-KO
    SSAT1 deficient
    HPLC
    high-performance liquid chromatography
    LC-MS
    liquid chromatography-mass spectrometry
    LC-MS/MS
    liquid chromatography-tandem mass spectrometry
    SpmTrien
    1,12-diamino-3,6,9-triazadodecane
    FID
    free induction decay
    TOF
    time of flight.

  • Received July 12, 2011.
  • Accepted August 30, 2011.
  • U.S. Government work not protected by U.S. copyright
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Drug Metabolism and Disposition: 39 (12)
Drug Metabolism and Disposition
Vol. 39, Issue 12
1 Dec 2011
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Research ArticleArticle

N-ACETYLATION OF TRIETHYLENETETRAMINE

Marc Cerrada-Gimenez, Janne Weisell, Mervi T. Hyvönen, Myung Hee Park, Leena Alhonen, Jouko Vepsäläinen and Tuomo A. Keinänen
Drug Metabolism and Disposition December 1, 2011, 39 (12) 2242-2249; DOI: https://doi.org/10.1124/dmd.111.041798

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Research ArticleArticle

N-ACETYLATION OF TRIETHYLENETETRAMINE

Marc Cerrada-Gimenez, Janne Weisell, Mervi T. Hyvönen, Myung Hee Park, Leena Alhonen, Jouko Vepsäläinen and Tuomo A. Keinänen
Drug Metabolism and Disposition December 1, 2011, 39 (12) 2242-2249; DOI: https://doi.org/10.1124/dmd.111.041798
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