Fatty acid stimulated N-demethylation of 1,2-dimethylhydrazine and tetramethylhydrazine by rat colonic mucosa.
A fatty acid stimulated, NADPH-independent pathway for the N-demethylation of 1,1-dimethylhydrazine (1,1-DMH) with the generation of HCHO was demonstrated in 10,000 g soluble fractions of colonic mucosal homogenates. Tetramethylhydrazine and, to a lesser extent, aminopyrine, but not 1,2-DMH or methylhydrazine, were also substrates for this reaction. Isolated superficial colonic epithelial cells metabolized 1,1-DMH at a faster rate than proliferative epithelial cells. Indomethacin, an inhibitor of cyclooxygenase activity, and 5,8,11,14-eicosatetraynoic acid (ETYA), an inhibitor of both cyclooxygenase and lipoxygenase activities, suppressed HCHO production from 1,1-DMH by 50 and 80%. However, in the presence of indomethacin or ETYA, arachidonate hydroperoxide stimulated HCHO formation. This suggested a peroxidative mechanism for 1,1-DMH metabolism, related in part to prostaglandin synthesis. A possible role for lipoxygenase activity in mediating 1,1-DMH metabolism was suggested by the ability of linoleate, which did not increase prostaglandin synthesis, to stimulate 1,1-DMH metabolism and by the fact that ETYA was more effective than indomethacin as an inhibitor of 1,1-DMH metabolism. The fatty acid stimulated pathway for N-demethylation was clearly distinct from the mixed function oxidase activities. NADPH did not stimulate 1,1-DMH metabolism to HCHO. 7,8-Benzoflavone or SKF-525A, inhibitors of cytochrome P-450, and methimazole, an inhibitor of N-demethylation catalyzed by the hepatic microsomal FAD-containing monooxygenase, did not suppress HCHO formation. To the extent that 1,1-DMH and tetramethylhydrazine reach the colon unchanged, the results suggest that fatty acid stimulated cooxidation pathways in colonic mucosa may contribute to the metabolism of these agents. Metabolism by superficial cells which are destined to slough may be an important defense mechanism against the toxic and carcinogenic actions of these hydrazines in colon.
D019813:1,2-Dimethylhydrazine; D015117:5,8,11,14-Eicosatetraynoic Acid / Q000494:pharmacology; D000818:Animals; D001091:Arachidonate Lipoxygenases; D003106:Colon / Q000201:enzymology*; D016861:Cyclooxygenase Inhibitors; D003640:Dealkylation; D004127:Dimethylhydrazines / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D005227:Fatty Acids / Q000494:pharmacology*; D005260:Female; D066298:In Vitro Techniques; D007213:Indomethacin / Q000494:pharmacology; D007413:Intestinal Mucosa / Q000201:enzymology*; D016859:Lipoxygenase Inhibitors; D008763:Methylhydrazines / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains
D016861:Cyclooxygenase Inhibitors; D004127:Dimethylhydrazines; D005227:Fatty Acids; D016859:Lipoxygenase Inhibitors; D008763:Methylhydrazines; D015117:5,8,11,14-Eicosatetraynoic Acid; C013705:tetramethylhydrazine; D001091:Arachidonate Lipoxygenases; D019813:1,2-Dimethylhydrazine; D007213:Indomethacin