Studies on the N-demethylation and O-de-ethylation of ethylmorphine by hepatic microsomes from male rats
Thompson, J.A.; Holtzman, J.L.
Drug Metabolism and Disposition the Biological Fate of Chemicals 5(1): 9-14
1977
ISSN/ISBN: 0090-9556 PMID: 13981 Document Number: 118142
On the basis of inhibition studies of the dealkylation of morphine and norcodeine, George and Tephly concluded that O-dealkylation and N-dealkylation are catalyzed by different enzymes. We have examined the microsomal dealkylation of 3-O-[1'-14Clethylmorphine by measuring HCHO colorimetrically and [1-14C]acetaldehyde radiometrically. We find that the KM for the O-de-ethylation is 57 muM, which is quite close to the KS(71 muM) for the type I binding of ethylmorphine in similar preparations. On the other hand, the KM for N-demethylation was 250 muM. Further, the N-demethylation was stoichiometric with the stimulation of both NADPH-cytochrome P-450 reductase and NADPH oxidase, whereas the sum of the N-demethylation and O-de-ethylation was significantly greater, suggesting that the O-de-ethylase activity does not involve stimulation of either of these two activities. Induction with phenobarbital increaesed N-demethylation 118% but did not affect O-de-ethylation. Finally, D2O inhibited the N-demethylase more than the O-de-ethylase.