Synthesis of isoornithines and methylputrescines. An evaluation of their inhibitory effects on ornithine decarboxylase.
2-(Aminomethyl)-4-aminobutyric acid (isoornithine), 3-methylisoornithine, and 2,3-dimethylisoornithine were not decarboxylated by liver ornithine decarboxylase (ODC, EC 4.1.1.17) of thioacetamide-treated rats but were good competitive inhibitors of the enzyme (Ki ranged from 0.72 to 1.79 mM). When assayed in vivo in the treated rats, the above mentioned isoornithines were also found to inhibit liver ODC when administered 1 h before sacrifice. When the methylputrescines formally derived from the decarboxylation of several isoornithines were assayed on rat liver ODC, it was found that only 2,3-dimethylputrescine decreased the enzymatic activity. When assayed in vivo, it was found to decrease ODC activity by 60%, when the latter was measured 1 h after administration. The effect was reverted 4 h after administration of the drug. Isoornithines were not taken up by H-35 hepatoma cells; hence they did not affect their ODC activity. 2,3-Dimethylputrescine however, was transported into the cells and significantly decreased its ODC activity.
D000818:Animals; D001667:Binding, Competitive; D006528:Carcinoma, Hepatocellular; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008113:Liver Neoplasms; D009952:Ornithine / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000378:metabolism; D065108:Ornithine Decarboxylase Inhibitors; D011700:Putrescine / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000378:metabolism; D051381:Rats; D013329:Structure-Activity Relationship; D013853:Thioacetamide / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D004791:Enzyme Inhibitors; D065108:Ornithine Decarboxylase Inhibitors; D013853:Thioacetamide; D009952:Ornithine; D011700:Putrescine