Differential stimulation of S-adenosylmethionine decarboxylase by difluoromethylornithine in the rat colon and small intestine

Abstract

The effects of chronic inhibition of ornithine decarboxylase (ODC) by the specific inhibitor difluoromethylornithine (DFMO) in the rat colon and small intestine on mucosal contents of polyamines, decarboxylated S-adenosylmethionine (decarboxylated AdoMet) and S-adenosylmethionine decarboxylase (AdoMet decarboxylase) activity were studied. Administration of 1% DFMO in the drinking water for 10 or 15 weeks resulted in inhibition of ODC and decreases in intracellular putrescine and spermidine contents in both proximal and distal segments of small intestine and colon. At both time points DFMO administration resulted in a dramatic stimulation of AdoMet decarboxylase activity and a rise in decarboxylated AdoMet content in the proximal and distal small-intestinal segments compared with controls, which was not seen in either colonic segment of DFMO-treated animals. This differential stimulation of AdoMet decarboxylase by DFMO in the small intestine and colon could not be entirely explained on the basis of differences in polyamine contents, which are known to regulate this enzyme activity. Kinetic and inhibition studies of AdoMet decarboxylase in control small and large intestine revealed that: (1) there was no difference in Vmax. values between the tissues; (2) the Km for AdoMet was higher in the small intestine than in the colon; and (3) the Ki for product inhibition by decarboxylated AdoMet was higher in the small intestine than in the colon. These results suggest that the differential stimulation of AdoMet decarboxylase by DFMO in the small intestine and colon may be due to different isoenzymes and could play a significant role in the regulation of polyamine contents throughout the gut.