Induction of spermidine/spermine N1-acetyltransferase by methylglyoxal bis(guanylhydrazone).
The anti-tumor agent methylglyoxal bis(guanylhydrazone) was found to be a competitive inhibitor of spermidine/spermine N1-acetyltransferase with a Ki of about 8 microM. 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 increase 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 polyamines 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) occurs via the induction of this 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 increase in this enzyme which occurs with higher doses may contribute to the very severe toxicity of methylglyoxal bis(guanylhydrazone).
D000123:Acetyltransferases / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D000818:Animals; D004790:Enzyme Induction; D005260:Female; D007668:Kidney / Q000201:enzymology; D007700:Kinetics; D008099:Liver / Q000201:enzymology; D008935:Mitoguazone / Q000494:pharmacology*; D009928:Organ Specificity; D011700:Putrescine / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D013095:Spermidine / Q000378:metabolism; D013096:Spermine / Q000378:metabolism; D013154:Spleen / Q000201:enzymology; D000099228:Diamine N-Acetyltransferase
D000123:Acetyltransferases; D008935:Mitoguazone; D011700:Putrescine; D013095:Spermidine; D013096:Spermine; D000099228:Diamine N-Acetyltransferase