Pathways of Metabolism

Of the many ingenious methods that have been used to follow these interconversions, or metabolic pathways, as they are called, we may cite two here which have, time and again, proved their utility. The first demands the selection of a substance which specifically blocks one of a series of enzymes acting in sequence. Consider the reaction sequence 

What is the effect of this If we were to analyse the tissue in the absence of the inhibitor of M-ase, we should only have found K and N present, for L and M were used as fast as they were made. But with the inhibitor present, analysis will reveal the presence of L and M as well. So we know that L and M must be formed en route between K and N. It is as if we had wanted to study the make and type of cars and lorries going past on a fast road. Under normal conditions, they go past too quickly for us to be able to spot the make. But if we put in a traffic light on the road, the vehicles slow down and stop, and finally a queue of stationary cars builds up which we can examine at leisure. 

Where can such inhibitors be obtained In some cases it is 

Study of the sequence K - N using such inhibitors shows that L and M are intermediates. We still do not know the order of the reaction. Either 

Radioactive isotopes used in this way are called tracers . Apart from carbon, the radioactive isotopes of phosphorus and sulphur, and sometimes also the isotopes of nitrogen, oxygen, and hydrogen, are used in metabolic studies. 

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Benke GM, Murphy SD. 1974. The influence of age and sex on the toxicity and multiple pathways of metabolism of methyl parathion and parathion in rats. Toxicol Appl Pharmacol 29 125. 

Generally, NAD-linked dehydrogenases catalyze ox-idoreduction reactions in the oxidative pathways of metabolism, particularly in glycolysis, in the citric acid cycle, and in the respiratory chain of mitochondria. NADP-linked dehydrogenases are found characteristically in reductive syntheses, as in the extramitochon-drial pathway of fatty acid synthesis and steroid synthesis—and also in the pentose phosphate pathway. 

Figure 22-9. Regulation of ketogenesis. -(Dshow three crucial steps in the pathway of metabolism of free fatty adds (FFA) that determine the magnitude of ketogenesis. (CPT-I, carnitine palmitoyltransferase-l.)...

Wegener WS, HC Reeves, R Rabin, SJ Ajl (1968) Alternate pathways of metabolism of short-chain fatty acids. Bacterial Rev 32 1-26. 

The potential for the metabolites that are formed to have the same masses as other parent compounds is another factor that limits the number of compounds that may be included in the cassette, as does the potential for drug-drug interactions [35]. Other limitations are the total dose that can be administered without saturating important pathways of metabolism or distribution, and the solubility of the compounds in the dosing formulation. However, there is a balance to be achieved as, if the dose of each component given is very low, it is likely that the analytical method will not have sufficient sensitivity to provide an accurate assessment of the pharmacokinetics. 

The answer is b. (Hardman, pp 868 869.) Persons with low hepatic iY-acetyltransferase activity are known as slow acetylators. A major pathway of metabolism of procainamide, which is used to treat arrhythmias, is iV-acetylation. Slow acetylators receiving this drug are more susceptible than normal persons to side effects, because slow acetylators will have higher-than-normal blood levels of these drugs N-acetylprocainamide, the metabolite of procainamide, is also active. 

The rate and pathways of metabolism change during development 535... 

Recent work in our laboratories has confirmed the existence of a similar pathway in the oxidation of vindoline in mammals (777). The availability of compounds such as 59 as analytical standards, along with published mass spectral and NMR spectral properties of this compound, served to facilitate identification of metabolites formed in mammalian liver microsome incubations. Two compounds are produced during incubations with mouse liver microsome preparations 17-deacetylvindoline, and the dihydrovindoline ether dimer 59. Both compounds were isolated and completely characterized by spectral comparison to authentic standards. This work emphasizes the prospective value of microbial and enzymatic transformation studies in predicting pathways of metabolism in mammalian systems. This work would also suggest the involvement of cytochrome P-450 enzyme system(s) in the oxidation process. Whether the first steps involve direct introduction of molecular oxygen at position 3 of vindoline or an initial abstraction of electrons, as in Scheme 15, remains unknown. The establishment of a metabolic pathway in mammals, identical to those found in Strep-tomycetes, with copper oxidases and peroxidases again confirms the prospective value of the microbial models of mammalian metabolism concept. 

Slatter JG, Rashed MS, Pearson PG, et al. Biotransformation of methyl isocyanate in the rat. Evidence for glutathione conjugation as a major pathway of metabolism and implications for isocyanate-mediated toxicities. Chem Res Toxicol 1991 4(2) 157—161. 

Kunz DA, Nagappan O, Silva-Avalos J, et al. 1992. Utilization of cyanide as a nitrogenous substrate by Pseudomonas fluorescens NCIMB 11764 Evidence for multiple pathways of metabolic conversion. Appl Environ Microbiol 58(6) 2022-2029. 

Greenberg, D.M., Ed. (1954). Chemical Pathways of Metabolism. Academic Press, New York. 

The pathways of metabolism of cis-chlordane appear to differ in these fish. Cichlids produce oxychlordane not produced by other fish. This may be due to the lack of formation of the intermediate, 1,2-dichlorochlordene in goldfish and bluegill (Fig. 6). 

Pohl L, Gillette J. 1984-1985. Determination of toxic pathways of metabolism by deuterium substitution. Drug Metab Rev 15 1335-1351. 

In a second study (Walton et al. 2001b), the magnitude of the interspecies differences in the internal dose of compounds for which glucuronidation is the major pathway of metabolism in either humans or in the test species was determined. There were major interspecies differences in the nature of the biological processes that influence the internal dose including route of metabolism, the extent of pre-systemic metabohsm, and enterohepatic recirculation. There was also a wide variability in the magnitude of differences in the internal dose for all of the test species. The mean values for the clearance ratios compared to humans were 4.5 for the mouse, 9.1 for the rat, 8.7 for the rabbit, and 9.7 for the dog. Thus, the fourfold default factor was exceeded for aU the species. 

FIGURE 2-2. Proposed Pathway of Metabolism of 1,3-DNB In Rats and Hamsters ... 

Variability in metabolism A subset (approximately 7%) of the population is devoid of CYP2D6, the enzyme responsible for the formation of the 5-hydroxymethyl metabolite of tolterodine. The identified pathway of metabolism for these individuals ( poor metabolizers ) is by dealkylation via cytochrome P450 3A4 (CYP3A4) to A/-dealkylated tolterodine. The remainder of the population is referred to as extensive metabolizers. Pharmacokinetic studies revealed that tolterodine is metabolized at a slower rate in poor metabolizers than in extensive metabolizers this results in significantly higher serum concentrations of tolterodine and in negligible concentrations of the 5-hydroxymethyl metabolite. 

The drug is concentrated in estrogen target tissues, such as the ovaries, uterus, vaginal epithelium, and breasts. Hydroxylation and glucuronidation of the aromatic rings are the major pathways of metabolism excretion occurs primarily in the feces. 

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