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At least 19 recordsLinked to original sources

PubMed1979

Studies on the N-demethylation and O-de-ethylation of ethylmorphine[6-3H] by male rat hepatic microsomes.

A sensitive and convenient radioassay for the in vitro determination of ethylmorphine N-demethylase and O-de-ethylase activity has been developed. Ethylmorphine[6-3H] was prepared by reduction of the corresponding morphinone in nearly quantitative yield. After incubation with hepatic microsomes from male rats, the reaction was terminated by the addition of 5 ml of acetone. The sample was saturated with potassium acetate and extracted twice with acetone giving complete extraction of the radiolabeled ethylmorphine and its metabolites. After the combined organic phases were evaporated, the samples were dissolved in methanol and applied to a Silica Gel GF plate with subsequent development in ethyl acetate-methanol-concentrated NH4OH. The amount of radioactivity detected for the morphine and norethylmorphine bands at zero time was approximately 0.05% of the original amount of labeled ethylmorphine added to the incubation media. Similarly, the Km values were 52 and 250 microns for the O- and N-dealkylation respectively, while the Vmax values were 5.0 and 1.8 nmol/mg of protein per min. Finally, with this assay we have observed constant specific activity for both the N- and O-dealkylation of ethylmorphine[6-3H] with as little as 10 micrograms of microsomal protein per ml of incubation media.

Animals↗

PubMed1977

Sex- and strain-dependent hepatic microsomal ethylmorphine N-demethylation in mice: the roles of type I binding and NADPH-cytochrome P-450 reductase.

The roles of type I binding and NADPH-cytochrome P-450 reductase in ethylmorphine demethylation were investigated in two strains of mice, using sex differences in these activities as a tool. In the CPB-SE strain, females metabolize ethylmorphine faster than males. Sex differences in cytochrome P-450 content and endogenous NADPH-cytochrome P-450 reductase activity were too small to account for this. On the other hand, the differences in the magnitudes of type I spectra and ethylmorphine-induced enhancement of cytochrome P-450 reduction were considerable larger than those in the rates of demethylation. All parameters, except endogenous cytochrome P-450 reduction, were modified in a similar way by testosterone pretreatment: in females they were depressed to the male level, whereas in males they remained unchanged. Castration had no effect in females and enhanced the activities in males. The CPB-V strain exhibited little or no sex differences in ethylmorphine demethylation, cytochrome P-450 content and endogenous cytochrome P-450 reduction. Testosterone pretreatment had little or no influence on these activities. Type I binding and reductase stimulation, however, showed sex differences, comparable to those observed in the CPB-SE strain, which were also abolished by testosterone. A relationship between reductase stimulation and type I binding was observed, which was, apparently, independent of sex or strain. It is concluded that androgen primarily influences the amount of cytochrome P-450-substrate complex formed, but that the reduction of this complex is not rate-limiting in the demethylation of ethylmorphine.

Animals↗

PubMed1978

Sex differences in the kinetic constants of ethylmorphine demethylation and type I binding to hepatic microsomal cytochrome P-450 in mice. The influence of castration and testosterone.

1. In the CPB-SE mouse strain sex differences were observed in the Km and Vmax of ethylmorphine demethylation and in the deltaAmax of its type I binding to cytochrome P-450. In the CPB-V strain a small sex difference in the Vmax of the demethylation was found, whereas Ks and deltaAmax of type I binding differed considerably. 2. Testosterone pre-treatment of female CPB-SE mice abolished all sex differences, as did castration of males, except in Vmax, which was partially decreased. In the CPB-V strain testosterone pre-treatment of females abolished sex differences in type I binding, but had no effect on ethylmorphine demethylation. 3. Km values exceeded the corresponding Ks in all cases and sex differences in deltaAmax far exceeded those in Vmax. It is concluded that the Km is determined not only by the Ks of type I binding and the reduction rate of the type I complex between ethylmorphine and cytochrome P-450. The larger sex differences in deltaAmax as compared with Vmax may be attributable to type I binding of ethylmorphine to cytochrome P-450 subspecies not involved in its demethylation.

Animals↗

PubMed1977

The influence of NADH on the ethylmorphine-N-demethylation in liver microsomes from control and phenobarbital-treated rats or different ages.

The ethylmorphine-N-demethylation by liver microsomes from control and phenobarbital-treated rats of different ages was investigated by means of adding NADPH in combination with NADH to the incubation medium. The rate of ethylmorphine-N-demethylation in the presence of NADPH without NADH is greater in adult than in young rats and greater in induced that in control rats. The higher the activity of ethylmorphine metabolism with NADPH alone the more it is abolsutely enhanced by NADH. The relative increase in ethylmorphine metabolism caused by NADH is equal in all groups of animals. It is concluded that there are no differences in the introduction of the second electron from NADH to the oxygenated cytochrome P-450 but there are differences in the concentration of cytochrome-substrate complex and, consequently, in the oxygenated cytochrome-substrate complex. The enhancing effect of NADH is higher at lower NADPH concentrations. In the presence of NADH, the NADPH concentrations necessary to obtain a msximum metabolic rate are lower than without NADH.

Animals↗

PubMed1977

Cause of decrease of ethylmorphine N-demethylase activity of lipid peroxidation in microsomes from the rat, guinea pig and rabbit.

There were marked differences among animal species between NADPH-dependent and ascorbic acid-Fe++-dependent lipid peroxidation. In NADPH-dependent lipid peroxidation, this activity occurred to the greatest extent in rats followed by guinea pigs and rabbits and such was much lower in rabbits than in guinea pigs. On the other hand, rabbit microsomes exhibited higher lipid peroxidation activity than guinea pigs in ascorbic acid plus Fe++ or Fe++-dependent lipid peroxidation although the activity was still lower than in rats. The ascorbic acid plus Fe++-stimulated lipid peroxidation produced a decrease in ethylmorphine N-demethylase activity which was closely related to ethylmorphine-enhanced NADPH-cytochrome P-450 reductase activity but was not related to the change of the apparent content of cytochrome P-450 in all animal species. These results indicate that decrease of NADPH-cytochrome P-450 reductase activity induces a decrease in ethylmorphine N-demethylase activity by lipid peroxidation.

Animals↗

PubMed1977

Ethylmorphine-N-demethylation by liver homogenate of newborn and adult rats; Enzyme kinetics and age course of Vmax and Km1.

Optimum incubation conditions for determination of ethylmorphine-N-demethylation with newborn and adult rat liver homogenate have been determined: 1 ml 1:20 liver homogenate in 1.15% KCl, 1 ml 0.1 M phosphate buffer with ethylmorphine, NADP, and glucose-6-P, final concentrations 10, 0.33 and 5 mM, respectively, no nicotinamide, no MgCl2, 1 ml 0.5 M phosphate buffer; 3 ml final volume, 20 min incubation time. With both age groups NADH increases the activity to the same extent. With NADPH, saturation could be achieved only with newborn liver, but not with adult liver homogenate. Postnatally, the activity increases about fivefold, with a break at the 10th day of life. The Lineweaver-Burk plot was linear with newborn liver homogenate, whereas for all other age groups the graphs showed an angle. Statistical analysis pointed out that a two-enzyme model fits the experimental data only insignificantly better than a one-enzyme model. From other experimental evidence and manifold reproduction without any exception of these results, however, it may be concluded that there are different monooxygenases which show different affinities towards one substrate (ethylmorphine) and which show different developmental patterns.

Age Factors↗

PubMedDate not supplied

Species, sex, and developmental differences in the O- and N-dealkylation of ethylmorphine by hepatic microsomes.

3-O-[1'-14C]Ethylmorphine and ethylmorphine, respectively, were used to measure O- and N-dealkylase activities of hepatic microsomes. The well-known sex difference in the rate of N-delakylation in mature rats was not observed with O-dealkylation, nor did O-dealkylase activity increase as male rats reached maturity, as is the case with N-dealkylase activity. Accordingly, O-dealkylation represents only about 20% of the total dealkylase activity (O- + N-) in mature male rats, but about 50% in mature female rats. A comparison of the O- and N-dealkylating activities of hepatic microsomes from rats, mice, guinea pigs, and rabbits showed that both the rates of O- and N-dealkylation and the ratio of the two reactions vary greatly among animal species. These studies contribute to the evidence that different cytochrome P-450-dependent mono-oxygenase systems are involved in the O- and N-dealkylation of opium alkaloids.

Aging↗

PubMedDate not supplied

Studies on the N-demethylation and O-de-ethylation of ethylmorphine by hepatic microsomes from male rats.

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.

Acetaldehyde↗

PubMed1978

Effect of vitamin A deficiency on hepatic microsomal and colon mucosal mixed function oxidase. IV--Influence on aflatoxin B1 metabolism, ethylmorphine and epoxide hydrase activity.

Male, weanling rats, divided into two groups were maintained for 45 days on a corn-based diet containing 5 mg vitamin A palmitate per kg diet (Group 1, normal animals) and without the vitamin (Group 2, dificient animals). Fifteen hours after the last feeding, the animals were decapitated and liver microsomes and colon mucosal epithelial homogenates were prepared and used to investigate the relative activities of the mixed function oxidase (MFO) and epoxide hydrase (EH) enzyme systems. The sequential metabolism of aflatoxin B1 (AFB1) and its epoxide AFBepox) product, respectively, were also estimated by measuring apparent maximal velocities (Vmax) and Michaelis constants (Km) for ethylmorphine (EM) N-demethylase and styrene oxide hydratase. The Vmax data indicated that MFO activity in the liver and colon was not rate-limiting in the two groups of animals but the reverse were observed with calculated reaction rates at concentrations above (0,03 mM) for EM N-demethylase only. In both organs, styrene oxide hydratase depict calculated reaction rates which are not rate-limiting for all the concentration range (0,001 to 3,00 mM). If these reaction rates are applied to AFB1 metabolism, it may be concluded that MFO and not epoxide hydrase (EH) activity is a critical agent under vitamin A deficiency in AFB1 toxicity and/or carcinogenesis. Measurements of AFT1 metabolism both in terms of substrate disappearance and product formation do not confirm this observation except for the production of AFR0 and compounds of unknown structure at the origin which may embody the critical factor(s) that promotes colon carcinogenesis under vitamin A deficiency.

Aflatoxins↗

PubMed1977