Ethylmorphine, demethylation

As well as the sex hormones already mentioned (see above), many other hormones seem to affect the metabolism of foreign compounds and therefore may have effects on toxicity. A number of pituitary hormones may directly, as well as indirectly, affect metabolism, for example, growth hormone, follicle-stimulating hormone, adrenocorticotrophic hormone, luteinizing hormone, and prolactin. Thus, hypophysectomy in male rats results in a general decrease in metabolism, but the effects of some of the individual hormones may depend on the sex of the animal and the particular enzyme or metabolic pathway. For example, adrenocorticotrophic hormone (ACTH) administration decreases oxidative metabolism in males but increases N-demethylation in female rats. Removal of the adrenal gland reduces metabolism, such as ethylmorphine demethylation and aniline 4-hydroxylation, and this can... 

Davies, D.S., P.L. Gigon, and J.R. Gillette (1969). Species and sex differences in electron transport systems in liver microsomes and their relationship to ethylmorphine demethylation. Life Sci. 8, 85 91. 

Arylhydrocarbon (benzo[a]pyrene) hydroxylase, benzphetamine-N-demethylation, ethylmorphine-N-demethylation, ethoxycoumarin-0-deethylation and ethoxyresorufin-0-deethylation were performed by published procedures (31,32,33,34), but optimized for use with trout microsomes as described previously (30, 35). Hemoprotein P-450 was determined by the procedure of Estabrook et al. (36) to avoid spectral interference by hemoglobin. Microsomal protein content was estimated either by the method of Ross and Shatz (37) or Lowry et al. (38), using bovine serum albumin standards. 

Ethylmorphine and benzphetamine are N-demethylated specifically by rodent cytochrome(s) P-450 (as opposed to cytochrome(s) P] -450) in the rat phenobarbital and the polyhalogenated biphenyls induce these demethylation reactions. However, it is clear that no such stimulation occurred in the rainbow trout (Table II). 

Anders, M.W. and Mannering, G.J. Kinetics of the inhibition of the N-demethylation of ethylmorphine by 2-diethylamino-ethyl 2,2-diphenyl valerate HC1 (SKF-525A) and related compounds. Mol. Pharmacol. (1966) 2 319-327. 

Figure 5 represents the in vitro metabolism of AFBi by rats fed diets containing either 5T or 20% casein. The production of the hydroxylated metabolites AFQi and AFMj is depressed in animals fed the low protein diet, the depression of metabolism is similar to that seen with the N-demethylation of ethylmorphine. An exception to the depressed production of AFMi and AFQi is the enhanced production of an unidentified aflatoxin, tentatively termed AFXi- This metabolite is retained at the origin on TLC... 

Drugs containing multiple functional groups are substrates for multiple drug-metabolizing enzymes and pathways. The N-demethylation vs O-dealkylation of ethylmorphine (Scheme 11.13) demonstrates that one reaction pathway may predominate. Propranolol is an example of a compound that forms multiple alternative metabolites (Scheme 11.14). 

An improved rapid procedure for the preparation of normorphine and norcodeine by A/-demethylation with phenyl chloroformate followed by hydrazine has been reported.An efficient synthesis of N-cyclobutylmethylnoroxymorphone (naltrexone) from thebaine, via 14-hydroxy-codeinone, has been described,as have preparations of A/-tetrahydrofurfuryl-noroxymorphone and of N-s-alkyl- and N-t-alkyl-normorphines. ° N-Demethylation and O-de-ethylation of 3-O-ethylmorphine by rat hepatic microsomes has been observed.A patent has been published covering the... 

Although 3-methylcholanthrene treatment stimulates the hydroxylation of 3.4-benzpyrene and zoxazolamine and the N-demethylation of 3-methyl-4-mono-methylaminoazobenzene (Table 8). it does not increase (in some cases decreases) the metabolism of ethylmorphine. hexobarbital, and aminopyrine. By contrast. 

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