Demethylation species differences

Species extrapolation. The model was developed and validated using the male Sprague-Dawley rat. No other species were tested and data from other species were not used to validate the model. The authors, however, suggest that this model would prove useful in developing better rate constants or other important determinants of species differences (for example, demethylation rates, which differ based on differences in gut flora and tissue enzyme levels). 

A better understanding of certain physiological and biochemical processes affecting mercury kinetics may help explain these species differences. Specific processes that appear likely determinants include differences in demethylation rates affecting methylmercury fecal secretion, reabsorption, and membrane transport (Farris et al. 1993) differences in tissue glutathione content and renal -glutamyltranspeptidase activity (Tanaka et al. 1991, 1992), differences in antioxidative status (Miller and Woods 1993), differences in plasma cysteine concentrations compared with other thiol-containing amino acids (Aschner... 

Studies by Klotz et al. (1975,1976a,b) suggest that biliary excretion of diazepam is unimportant in man, but there is some evidence (see above) for species differences (Klotz etal., 1975,1976a van der Kleijn et al., 1971). Urinary excretion of diazepam is mainly in the form of sulphate and glu-curonide conjugates (Mandelli et al., 1978). The main metabolic pathway is demethylation and hydroxylation to metabolites with CNS depressant activity in animals and man. These metabolites are desmethyldiazepam and oxazepam. 

Species differences in the demethylation of amidopyrine by liver microsomes are summarized in Table 11. 

Figure 3 shows the ratio of (mono-OH-MXQ/(mono- -I- bis-OH-MXC), where the values of mono- and bis- demethylated metabolites also include the amounts of their corresponding conjugates. After reaction in each animal preparation, more than 80% of demethylated metabolites were detected as a mono-demethylated form for mouse and quail, about 50% for trout, and less than 5 % for rat. The results indicate that O-demethylase enzyme(s) in rat can easily remove both methyl groups from the parent molecule, but only one methyl group can be preferably demethylated by the enzyme(s) in mouse and quail. Rainbow trout produces almost equal amounts of mono- and bis- demethylated metabolites. These facts suggest that there are species differences in the manner of phase I oxidative demethylation, and such differences are probably due to the... 

There may be species differences in the induction of drug metabolism in extra-hepatic tissues. For example, treatment of rabbits with phenobarbital significantly increases the hydroxylation and N-demethylation of N-methylaniline and the microsomal protein and cytochrome P-4S0 content of liver and kidney microsomes, but not in lung and small intestine. However, treatment of rats with phenobarbital, 3,4-benzpyrene, or DDT does not significantly affect the levels of cytochrome P-4S0 or drug metabolism in kidney microsomes. 

In the rat, development to adult levels of activity takes about 30 days after which levels decline toward old age. In humans, however, hydroxylase activity increases up to the age of 6 years, reaching levels greater than those in the adult, which only decrease after sexual maturation. Thus the elimination of antipyrine and theophylline was found to be greater in children than in adults. It should be noted, however, that proportions of isoenzymes may be very different in neonates from the adult animal, and the development of the isoenzymes may be different. Thus, in the rat there seem to be four types of development for phase 1 metabolizing enzymes linear increase from birth to adulthood, type A (aniline 4-hydroxylation) low levels until weaning, then an increase to adult levels, type B (N-demethylation) rapid development after birth followed by rapid decline to low levels in adulthood, type C (hydroxylation of 4-methylcoumarin) and rapid increase after birth to a maximum and then decline to adult levels, type D. Patterns of development may be different between sexes as well as between species. For example, in the rat, steroid 16-a-hydroxylase activity toward androst-4-ene-3,17-dione develops in type B fashion in both males and females, but in females, activity starts to disappear at 30 days of age and is undetectable by 40 days. It seems that the monooxygenase system develops largely as a unit, with the rate dependent on species and sex of the animal and the particular substrate. 

LMW yeast Se compounds is given [46], It was assumed that adenosylselenoho-mocysteine (AdoSe-Hcy), which had been identil>ed in yeast by different authors [51, 63], could be a demethylation product of adenosylselenomethionine (AdoSe-Met). The latter compound is formed when selenomethionine enters the pathway of its S analog in enzymatic transmethylation. For the safe detection of AdoSe-Met, an LMW fraction of Se enriched yeast was obtained by homogenization of fresh cells and precipitation of proteins with HCIO4 at 0°C. The identification and/or conf>rmation of species observed by ion-pairing (IP) HPLC-ICP-MS was accomplished by spiking the samples with both commercial and laboratory-synthesized standards, and by electrospray (ES) MS. 

Ketamine, a dissociative anaesthetic, is administered as a racemic mixture (present in the parenteral preparation) and is initially metabolized by the liver to AT-desmethylketamine (metabolite I), which in part is converted by oxidation to the cyclohexene (metabolite II) (Fig. 1.5). The major metabolites found in urine are glucuronide conjugates that are formed subsequent to hydroxylation of the cyclohexanone ring. As the enantiomers differ in anaesthetic potency and the enantioselectively formed (metabolite I has approximately 10% activity of the parent drug) interpretation of the relationship between the anaesthetic effect and disposition of ketamine is complicated. On a pharmacodynamic basis, the S(+) enantiomer is three times as potent as the R(-) enantiomer (Marietta et al., 1977 Deleforge et al., 1991), while the enantiomer that undergoes N-demethylation (hepatic microsomal reaction) differs between species (Delatour et al, 1991). Based on the observed minimum anaesthetic... 

Very nearly the same 10 kJ moH destabilization for gas phase ortho- vs. para-tert-butylation of phenol is seen in the enthalpies of formation of variously substituted tert-butylmethylphenols shown in Table 3, and indeed the difference between the enthalpies of formation of these species and their demethylated counterparts, ca 30 kJ moH, reflects the 33 kJ mol difference between the enthalpies of formation of gaseous toluene and benzene. Said differently, the 5(OH/H) increment satisfactorily reproduces the enthalpy of formation of these teri-butylmethylphenols when acknowledgment is made for the ca 10 kJ mol destabilization or strain associated with tert-Bu and OH ortho to each other. ... 

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