POLYAMINES AND BIOSYNTHETIC-ENZYMES IN THE RAT INTESTINAL-MUCOSA AND THE INFLUENCE OF METHYLGLYOXAL-BIS(GUANYLHYDRAZONE)

  • 1 January 1980
    • journal article
    • research article
    • Vol. 40  (7) , 2330-2335
Abstract
The use of methylglyoxal-bis(guanylhydrazone) (MGBG) in the clinical treatment of myeloid and lymphoid disorders, including leukemia, has been limited by severe host toxicity to renewing tissues, particularly the intestinal mucosa. Since the drug is a potent inhibitor of spermidine biosynthesis, the distributions of ornithine and S-adenosylmethionine decarboxylases and polyamine pools were characterized in the rat intestinal mucosa in an attempt to discern the basis for MGBG toxicity. A method of epithelial cell isolation in which fractions of cells are sequentially collected in a villus tip-to-crypt gradient was used. Ornithine decarboxylase activity was highest in the villus tip region and unexpectedly lowest in the crypts, while S-adenosylmethionine decarboxylase activity showed the opposite pattern. Intracellular polyamine pools were uniform along the gradient corresponding to the villus length and increased appreciably in the crypt region. The relative concentrations of the individual polyamines were highest in the crypts, with spermidine and spermine being nearly equivalent in all regions. At 24 h after a single i.p. injection of MGBG (50 mg/kg), S-adenosylmethionine decarboxylase activity increased markedly, especially in the crypt region (.apprx. 50-fold), while ornithine decarboxylase activity also increased but to a lesser extent. Putrescine pools were most affected by MGBG and were elevated 5- to 6-fold, especially in the crypt region. An alteration of polyamine biosynthesis by MGBG apparently is involved in the antiproliferative toxicity of the drug.