Metabolic reactions, inhibition

Calu-3 cells have shown the ability to perform fatty acid esterification of budes-onide [132], In pre-clinical studies, this esterification results in a prolonged local tissue binding and efficacy, which is not found when the esterification is inhibited [133]. The precise mechanism remains undefined in that the identity of specific enzyme(s) responsible for this metabolic reaction is unclear [134], Assessment of the potential toxicity and metabolism of pharmaceuticals and other xenobiotics using in vitro respiratory models is still at its infancy. The development of robust in vitro human models (i.e., cell lines from human pulmonary origin) has the potential to contribute significantly to better understanding the role of biotransformation enzymes in the bioactivation/detoxication processes in the lung. 

Nateglinide is predominantly metabolized by the cytochrome P450 isozyme CYP2C9 (70%) and to a lesser extent CYP3A4 (30%). Nateglinide is a potential inhibitor of the CYP2C9 isoenzyme in vivo as indicated by its ability to inhibit the in vitro metabolism of tolbutamide. Inhibition of CYP3A4 metabolic reactions was not detected in in vitro experiments. 

The compound sulfanilamide exhibits a structural similarity to para-amino benzoic acid (PABA). Woods and Fields proposed the theory that sulfonamides, being structurally similar to PABA, inhibit bacterial folate synthetase so that folic acid is not formed which is needed for a number of metabolic reactions. Folic acid derived from PABA is essential for bacterial metabolism. Sulfonamides inhibit the enzyme folic acid synthetase which is... 

The alkylating agents can transfer an alkyl radical to a suitable receptor site. Alkylation of DNA within the nucleus represent the major interactions which will lead to cell death. These agents react chemically with sulfhydryl, carboxyl, amino and phosphate groups of other cellular nucleophiles in the cells which make them unavailable for the normal metabolic reactions. Alkylating agents react with nucleic acid and inhibit... 

Figure 11-1 Some control elements for metabolic reactions. Throughout the book modulation of the activity of an enzyme by allosteric effectors or of transcription and translation of genes is indicated by dotted lines from the appropriate metabolite. The lines terminate in a minus sign for inhibition or repression and in a plus sign for activation or derepression. Circles indicate direct effects on enzymes, while boxes indicate repression or induction of enzyme synthesis.

On the other hand, drugs may inhibit the metabolism of other drugs. For example, allopurinol (a xanthine oxidase inhibitor that inhibits the synthesis of uric acid) increases the effectiveness of anticoagulants by inhibiting their metabolism. Chloramphenicol (a potent inhibitor of microsomal protein synthesis) and cimetidine (an H2-receptor blocker used in acid-pepsin disease) have similar properties. In addition, drugs may compete with each other in metabolic reactions. In methyl alcohol (methanol) poisoning, ethyl alcohol may be given intravenously to avert methanol-induced blindness and minimize the severe acidosis. Ethyl alcohol competes with methyl alcohol for... 

Because the enzyme functions as a catalyst, its inhibition or inactivation may decrease the rate of a particular metabolic reaction. The reduction in the rate of this reaction may inhibit the pathway in which this reaction occurs and, in turn, result in the depletion of a product or the accumulation of precursors or intermediates. Changes in 02 or C02 exchange, pools of various metabolites, and the metabolism of glucose (both catabolism and incorporation into cell wall polysaccharides) that have been observed also support this hypothesis. 

The elucidation of metabolic pathways has often been aided by the use of genetic mutations, or specific, chemical inhibitors that result in the blockage of a specific, metabolic reaction along the pathway such inhibition can sometimes lead to the accumulation of prior intermediates, and thus facilitate their isolation and identification. 

Methotrexate [meth oh TREX ate] (MTX) is structurally related to folic acid and acts as an antagonist of that vitamin by inhibiting dihydrofolate reductase1, the enzyme that converts folic acid to its active, coenzyme form, tetrahydrofolic acid (FH4) it therefore acts as an antagonist of that vitamin. Folate plays a central role in a variety of metabolic reactions involving the transfer of one-carbon units. (Figure 38.7)2. 

Alteration of a metabolic pathway, for example some sulphonamide-resistant bacteria switch to using pre-formed fohc acid, rather than synthesise the precursor para-aminobenzoic acid (PABA), which is the reaction inhibited by sulphonamides. 

CARBAMAZEPINE H2 RECEPTOR BLOCKERS -CIMETIDINE, FAMOTIDINE, RANITIDINE t plasma concentrations of phenytoin and risk of adverse effects including phenytoin toxicity, bone marrow depression and skin reactions Inhibition of metabolism via CYP2C9 and CYP2C19 Use alternative acid suppression (e.g. ranitidine) or warn patients that effects last about 1 week. Consider monitoring carbamazepine levels, and adjust dose as necessaiy... 

Hundreds of metabolic reactions take place simultaneously in cells. There are branched and parallel pathways, and a single biochemical may participate in severm distinct reactions. Through mass action, concentration changes caused by one reaction may effect the kinetics and equilibrium concentrations of another. In order to prevent accumulation of too much of a biochemical, the product or an intermediate in the pathway may slow the production of an enzyme or may inhibit the activation of enzymes regulating the pathway. This is termed feedback control and is shown in Fig. 24-1. More complicated examples are known where two biochemicals act in concert to inhibit an enzyme. As accumulation of excessive amounts of a certain biochemical may be the key to economic success, creating mutant cultures with defective metabolic controls has great value to the production of a given product. 

In hepatic microsomes, omeprazole inhibited cytochrome P450-mediated metabolic reactions in vitro. This effect was comparable to the inhibition caused by cimetidine with respect to the extent of the inhibitory effect and the effective concentrations [110]. Under well-defined clinical conditions, an... 

Dendrites are the (filamentous) terminal portions of neuron that bind neurotransrrritter chemicals migrating across the synaptic gaps separating neurons. Depending on the type and function of a particular neuron, neurotransmitters may cause or inhibit the transmission of neural impulses. The cell body contains the cell nucleus and a concentration of cellular organelles. The cell body is the site of the normal metabolic reactions that allow the cell to remain viable. Neurotransmitters synthesized within the cell body are transported to the axon terminus by microfilaments and microtubules. 

With modest increase in intracellular ROS levels, activation of NF-kB takes place, which protects the cell against oxidative stress [45], Direct root of ROS participation in signal transduction from cell membrane to intracellular metabolic reactions were recently described. Among them - activation of potential-dependent K-channels and variation of membrane potential, inhibition of cellular protein phosphatases and restriction of activity of MAP-kinase [49]. Such view on intracellular role of ROS consider them as second messengers, which together with cyclic nucleotides, calcium ions, and other biologically active compounds provides adequate cell response to the outer signals. 

Non-IgE-mediated anaphylactic reactions to polyacrylonitrile membranes have been reported (2,3). The effects are enhacing in those using ACE inhibitors (4,5), perhaps because of an effect of bradykinin (6), which is released by the membranes (2,8,9) and whose metabolism is inhibited by ACE inhibitors. The effects also occur to a lesser extent in those taking angiotensin receptor antagonists (7) and in those with Cl esterase inhibitor deficiency (10). Treating the membranes with polyethyleneimine prevents bradykinin release (11). 

TBTO undergoes a condensation reaction with cellulose to form a tributyltin alkoxide (57). This reaction with cellulose could prevent metabolism by inhibiting the extracellular enzymes of the wood-destroying fungi. However, such a reaction is unlikely to be initiated in situ because the alkoxide is highly susceptible to hydrolysis (58). 

This approach has the possible advantage over using a combination of two inhibitors, that it eliminates all the pharmacokinetic variables and synchronizes the inhibitory action at the two enzyme sites. However, there is a competition between the two enzymes for the inhibitor, since each molecule of the latter can bind only to one enzyme therefore, the relative extent of inhibition of the two metabolic reaction steps depends on the relative affinities (ratio of the Kj values) of the inhibitor for the two enzymes. This, of course, is determined by the structure of the inhibitor, and it should be amenable to change via structural modifications (e.g., by providing 71 with a hydroxyalkyl side chain and thus making it more closely similar in structure to riboflavin and more antagonistic to it). Although this approach has inherent limitations in scope, its further exploration appears to be of interest. 

Biotransformation, especially phase I metabolic reactions, cannot be assumed to be synonymous with detoxification because some drugs (although a minority) and xenobiotics are converted to potentially toxic metabolites (e.g. parathion, fluorine-containing volatile anaesthetics) or chemically reactive intermediates that produce toxicity (e.g. paracetamol in cats). The term lethal synthesis refers to the biochemical process whereby a non-toxic substance is metabolically converted to a toxic form. The poisonous plant Dichapetalum cymosum contains monofluoroacetate which, following gastrointestinal absorption, enters the tricarboxylic acid (Krebs) cycle in which it becomes converted to monofluorocitrate. The latter compound causes toxicity in animals due to irreversible inhibition of the enzyme aconitase. The selective toxicity of flucytosine for susceptible yeasts (Cryptococcus neoformans, Candida spp.) is attributable to its conversion (deamination) to 5-fluorouracil, which is incorporated into messenger RNA. 

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