Polyamines and Biosynthetic Enzymes in the Rat Intestinal Mucosa and the Influence of Methylglyoxal-bis(guanylhydrazone)1

The use of methylglyoxal-bis(guanylhydrazone) (MGBG) in the clinical treatment of myeloid and lymphoid disorders has been limited by severe host toxicity to renewing tissues, partic ularly the intestinal mucosa. Since the drug is a potent inhibitor of spermidine biosynthesis, the distributions of ornithine and S-adenosylmethionine decarboxylases and polyamine pools have been 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 sequen tially collected in a villus tip-to-crypt gradient was used. Orni thine decarboxylase activity was highest in the villus tip region and unexpectedly lowest in the crypts, while S-adenosylmeth ionine 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. Twenty-four hr after a single i.p. injection of MGBG (50 mg/kg), S-adenosyl methionine decarboxylase activity increased markedly, espe cially in the crypt region (~50-fold), while ornithine decarbox ylase activity also increased but to a lesser extent. Putrescine pools were most affected by MGBG and were elevated 5to 6fold, especially in the crypt region. The results are consistent with an alteration of polyamine biosynthesis by MGBG being involved in the antiproliferative toxicity of the drug.