Induction of spermidine/spermine N1-acetyltransferase by methylglyoxal bis(guanylhydrazone)

Anthony E. Pegg, Bradley G. Erwin, Lo Persson

Research output: Contribution to journalArticle

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Abstract

The anti-tumor agent methylglyoxal bis(guanylhydrazone) was found to be a competitive inhibitor of spermide/spermine N1-acetyltransferase with a Ki of about 8 μM. Treatment of rats with this drug lead to a very large increase in the total amount of spermidine/spermine N1-acetyltransferase in liver, kidney and spleen. The total increase as measured using a specific antiserum amounted to 700-fold in liver and 100-fold in kidney within 18 h of treatment with 80 mg/kg doses. At least part of this induction was due to a pronounced increased in the half-life of the acetyltransferase which increased from 15 min to more than 12 h. The very large increase in the amount of the enzyme is likely to overwhelm the direct inhibition, and a net increase in the acetylation of polyamine by this enzyme would be expected to occur after treatment with methylglyoxal bis(guanylhydrazone). The acetylated polyamines are known to be rapidly degraded by polyamine oxidase producing putrescine. Direct evidence that a substantial part of the increase in the content of putrescine in the liver of rats treated with methylglyoxal bis(guanylhydrazone) occures via the induction of thie acetylase/oxidase pathway was obtained. These results indicate that methylglyoxal bis(guanylhydrazone) affects cellular polyamine levels not only by means of its inhibitory effect on S-adenosylmethionine decarboxylase and diamine oxidase but also by the induction of spermidine/spermine N1-acetyltransferase. They also raise the possibility that the enormous increse in this enzyme which occurs with higher doses may contribute to the very severe toxicity of methylglyoxal bis(guanylhydrazone).

Original languageEnglish (US)
Pages (from-to)111-118
Number of pages8
JournalBBA - General Subjects
Volume842
Issue number2-3
DOIs
StatePublished - Oct 17 1985

Fingerprint

Mitoguazone
Acetyltransferases
Spermidine
Spermine
Polyamines
Liver
Putrescine
Rats
Enzymes
Adenosylmethionine Decarboxylase
Acetylesterase
Amine Oxidase (Copper-Containing)
Kidney
Acetylation
Half-Life
Toxicity
Tumors
Immune Sera
Oxidoreductases
Spleen

All Science Journal Classification (ASJC) codes

  • Biophysics
  • Biochemistry
  • Molecular Biology

Cite this

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abstract = "The anti-tumor agent methylglyoxal bis(guanylhydrazone) was found to be a competitive inhibitor of spermide/spermine N1-acetyltransferase with a Ki of about 8 μM. Treatment of rats with this drug lead to a very large increase in the total amount of spermidine/spermine N1-acetyltransferase in liver, kidney and spleen. The total increase as measured using a specific antiserum amounted to 700-fold in liver and 100-fold in kidney within 18 h of treatment with 80 mg/kg doses. At least part of this induction was due to a pronounced increased in the half-life of the acetyltransferase which increased from 15 min to more than 12 h. The very large increase in the amount of the enzyme is likely to overwhelm the direct inhibition, and a net increase in the acetylation of polyamine by this enzyme would be expected to occur after treatment with methylglyoxal bis(guanylhydrazone). The acetylated polyamines are known to be rapidly degraded by polyamine oxidase producing putrescine. Direct evidence that a substantial part of the increase in the content of putrescine in the liver of rats treated with methylglyoxal bis(guanylhydrazone) occures via the induction of thie acetylase/oxidase pathway was obtained. These results indicate that methylglyoxal bis(guanylhydrazone) affects cellular polyamine levels not only by means of its inhibitory effect on S-adenosylmethionine decarboxylase and diamine oxidase but also by the induction of spermidine/spermine N1-acetyltransferase. They also raise the possibility that the enormous increse in this enzyme which occurs with higher doses may contribute to the very severe toxicity of methylglyoxal bis(guanylhydrazone).",
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Induction of spermidine/spermine N1-acetyltransferase by methylglyoxal bis(guanylhydrazone). / Pegg, Anthony E.; Erwin, Bradley G.; Persson, Lo.

In: BBA - General Subjects, Vol. 842, No. 2-3, 17.10.1985, p. 111-118.

Research output: Contribution to journalArticle

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