Metabolic specificity

The coupling of solute transport in the GI lumen with solute lumenal metabolism (homogeneous reaction) and membrane metabolism (heterogeneous reaction) has been discussed by Sinko et al. [54] and is more generally treated in Cussler s text [55], At the cellular level, solute metabolism can occur at the mucosal membrane, in the enterocyte cytosol, and in the endoplasmic reticulum (or microsomal compartment). For peptide drugs, the extent of hydrolysis by lumenal and membrane-bound peptidases reduces drug availability for intestinal absorption [56], Preferential hydrolysis (metabolic specificity) has been targeted for reconversion... 

It may come as a surprise that CO is synthesized by the human body and has roles in human metabolism. Specifically, an enzyme that degrades heme, a constituent of hemoglobin, our oxygen-transporting protein, makes CO, which is a neurotransmitter. Much more about neurotransmitters follows in chapter 21 when we talk about the central nervous system. For the present, just understand that specialized cells known as neurons are the conduits for communication in the nervous system. Neurotransmitters are small molecules that relay information from one neuron to another. Neurotransmitter CO is made, functions, and is quickly destroyed. Personally, I find it surprising that CO has such a critical role in the nervous system. Surprised or not, there it is and there is no doubt about it. 

It has been shown that fish oil can not only suppress proinflammatory mediators but also can increase the anti-inflammatory ones such as adiponectin (Duda et al., 2009 Kalupahana et al., 2010b). Increased adipo-nectin levels can reduce inflammation and beneficially improve the metabolism. Specifically, the increased levels of adiponectin can significantly reduce the insulin resistance. Oster et al. (2010) showed that DHA increases cellular adiponectin mRNA and secreted adiponectin protein in 3T3-L1 adipocytes, possibly by a mechanism involving PPARy. A recent dietary intervention study conducted on healthy Japanese female subjects by Kondo et al. (2010) showed that a fish-based diet intervention increased the serum adiponectin concentration in young, nonobese, healthy Japanese female subjects. Also, the same study indicated that the increment in serum -3 PUFA may regulate the serum adiponectin concentration (Kondo et al., 2010). 

Isosteric substitution of the C-2 hydrogen atom of valproic acid (12) with a fluorine atom affords 2-fluorovalproic acid (22), which causes significantly less hepatoxicity than valproic acid, although a reduction in anticonvulsant properties is also observed [59, 60]. The hepatoxicity of 12 involves hepatic cytochrome P450-mediated metabolism to its 4-ene metabolite (14), which undergoes further metabolism, specifically mitchondrial (3-oxidation, to provide ( )-2-propyl-2,4-pentadienoic add (23), a reactive electrophilic metabolite [59, 60]. 

Food products in which the compound is used Has the compound been registered in two or more countries Has the manufacturer made a commitment to provide data List of data (toxicology, metabolism, specifications) available Date on which data could be submitted to JECFA... 

The endoplasmic reticulum is composed of a convoluted network of channels and so has a large surface area. Apart from cytochromes P-450, the endoplasmic reticulum has many enzymes and functions, besides the metabolism of foreign compounds. These include the synthesis of proteins and triglycerides and other aspects of lipid metabolism and fatty acid metabolism. Specific enzymes present on the endoplasmic reticulum include cholesterol esterase, azo reductase, glucuronosyl transferase, NADPH cytochromes P-450 reductase and NADH cytochrome b5 reductase and cytochrome b5. A FAD-containing monooxygenase is also found in the endoplasmic reticulum, and this is discussed later in this chapter. 

Insulin is a large polypeptide of 51 amino acids arranged in a specific sequence and configuration. The primary effect of insulin is to lower blood glucose levels by facilitating the entry of glucose into peripheral tissues. The effects of insulin on energy metabolism, specific aspects of insulin release, and insulin s mechanism of action are discussed here. 

It was the identification of a group of subjects unable to metabolize debrisoquine (118,119), resulting in a potentially life-threatening drop in blood pressure, which lead to the identification of the CYP2D6 polymorphism (120). Debrisoquine is metabolized specifically by CYP2D6 (121) to produce 4-hydroxy debrisoquine. 

Gao and Hansch (1996) reported examples of P450 metabolism, specifically N-demethylation, where the overall rate of the reaction for the isolated enzyme, increased with increasing lipophilicity (as measured by log Kow). Further, it was shown to be independent of the electron donating or withdrawing effects of substituents, which appeared to have approximately equal and opposite effects on the two components, substrate binding, and reaction rate. For microsomes in vitro the lipophilicity was a particularly significant factor. 

Serum concentration monitoring of various drugs administered to pediatric patients may appropriately give information about the drug but not its metabolites. This may be a problem when children metabolize specific drugs differently than adults with resulting differences in metabolite concentrations or the presence of different metabolites. This has been noted when premature infants... 

A number of different members of the nuclear-receptor superfamily regulate lipid metabolism. Specific small molecules are typical activators. Such molecules can be either synthesized inside the target cell, diffuse into the cell, or be transported into the cell. One example is FXR, which is activated by binding of bile acids. FXR is expressed in hepato-cytes and intestinal epithelial cells. Is the source of bile acid that activates FXR cell synthesized, cell imported, or a combination of the two Rather than giving specific names of proteins whose synthesis is regulated by FXR, predict classes of proteins whose synthesis should be regulated by a bile acid-activated nuclear receptor. 

The recent establishment of a link between ribonucleotide metabolism, specifically the synthesis of the cellular metabolite, diadenosine tetraphosphate, and its relationships with adenosine diphosphate-ribosylation reactions in the cell, presents a significant new target. 

Microphysiometry is a technique where a small population of cells or tissues is sealed in a micro or nanofluidic environment capable of sustaining cellular activity while a sensing element is employed to provide real-time and continuous measurement of extracellular analytes. The multi-analyte microphysiometer (MAMP) was developed to allow for real-time detectimi of changes in cellular metabolism, specifically monitoring four analytes central to aerobic and anaerobic respiration. The instrument, which is... 

This study hypothesized that obesity and diabetes occur because glucose absorbed by cells is not completely metabolized specifically, metabolic syndrome should not develop if cells completely metabolize glucose. Thiamine (vitamin Bi) acts as a lubricant for carbohydrate metabolism and the amount of catalytic thiamine absorbed must necessarily increase if glucose is to be metabolized in large quantities. We studied thiamine, an important element in combating metabolic syndrome, and the genes concerned with metabolic and functional disorders, as well as the factors related to obesity and diabetes. The aim of this study was to bridge the gap between basic research and medical practice. 

The routes of elimination of paclitaxel have not been fully established in humans. Only a small proportion of the drug (1.3-13%) is excreted unchanged in the urine [23 j. The main route of elimination appears to be via hepatic metabolism (specifically CYP3A4 and CYP2C8 activity) and biliary clearance. The three major metabolites of paclitaxel are 6n-hydroxy-paclitaxel, 3 -para-hydroxypaclitaxel, and 6a-3 -para-dihydroxypaclitaxel [24 ]. After intravenous administration of paclitaxel, the amounts of each metabolite excreted via the feces were 26%, 2%, and 6% respectively [2 ]. The metabolites of paclitaxel do not have significant cytotoxic properties themselves [25 ]. 

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