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Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)
 
 
 
 
 

Spermidine/spermine n(1)-acetyltransferase catalyzes amantadine acetylation.

Amantadine acetylation was demonstrated to occur both in vivo and in vitro using transgenic male mice overexpressing spermidine/spermine N(1)-acetyltransferase (SSAT). We previously reported that neither NAT1 nor NAT2 was responsible for catalyzing acetylation of the primary amine group of amantadine. We hypothesized that the inducible polyamine-catabolizing enzyme, SSAT, was an alternate pathway for acetylating amantadine. Transgenic mice injected s.c. with 3 mg/kg amantadine excreted 4.5 +/- 1% (mean +/- S.E.) of the administered dose as acetylamantadine in 24-h urine samples while, by contrast, nontransgenic control mice failed to excrete any detectable acetylamantadine in their urine. In vitro studies with the cytosolic liver fraction from transgenic mice as the source of SSAT demonstrated spermidine acetylation catalytic activity with an apparent K(m) = 267 +/- 46 microM and V(max) = 0.009 +/- 0.002 nmol/min/mg of protein. Amantadine competitively inhibited spermidine acetylation with an apparent K(i) = 738 +/- 157 microM. Incubation of amantadine, SSAT, and an acetyl CoA-regenerating system produced modest amounts of acetylamantadine. The NAT2 substrate, sulfamethazine, inhibited spermidine acetylation with a calculated K(i) = 3.5 mM, suggesting that SSAT may be an alternate pathway for acetylation of NAT2 substrates. The NAT1 substrate, p-aminobenzoic acid, had no inhibitory effect. These results provide evidence that amantadine can be acetylated by SSAT and may be a specific drug substrate for this enzyme. Further investigation of the role of SSAT as a potential drug-metabolizing pathway is warranted.[1]

References

  1. Spermidine/spermine n(1)-acetyltransferase catalyzes amantadine acetylation. Bras, A.P., Jänne, J., Porter, C.W., Sitar, D.S. Drug Metab. Dispos. (2001) [Pubmed]
 
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