Metabolic pathways altering

Such an enzyme under normal steady-state conditions tends to have the concentrations of its substrates and products at or near to their equilibrium values. Any enzyme enhances equally both the forward and the reverse rates of its catalyzed reaction. Those enzymes that catalyze seemingly irreversible reactions usually involve hydrolysis and since the water concentration in cells and tissues is thousands of times greater than metabolites, the equilibrium position of these reactions is poised in favor of the forward or hydrolytic process. In reactions not involving water, the net direction of the reactions depends on the relative concentration of the substrates and products. If the activity of the enzyme is sufficiently high, relative to others in a metabolic pathway, altering the activity of the enzyme simply makes both the forward and reverse reactions go faster, thus maintaining a pseudo-equilibrium. 

Metabolic pathway alterations Cellular transfection Viral gene delivery Antisense technology RNA interference... 

The biotransformation of a given chemical compound in experimental animals and in humans may differ. Furthermore, high doses of chemical compounds are used in studies with experimental animals, and this may cause alterations in biotransformation of the tested chemicals that do not occur at the lower doses relevant to the human exposure situation. For example, a metabolic pathway dominating at low doses may become saturated, and a salvage metabolic pathway, e.g., one that produces reactive intermediates of the compound, may become involved in the biotransformation of the chemical. Since this intermediate could never be produced at the exposure levels encountered in humans, the overall result... 

In order to develop a rational approach to improving rates of metabolite production, it is necessary to consider the fate of the nutrients that are required for its synthesis. However, overcoming the major flux control points within a metabolic pathway may not lead to metabolite overproduction if the energetic consequences of the alteration are unfavourable to the organism. 

Plants are constantly subject to adverse environmental conditions such as drought, flooding, extreme temperatures, excessive salts, heavy metals, high-intensity irradiation and infection by pathogenic agents. Because of their immobility, plants have to make necessary metabolic and structural adjustments to cope with the stress conditions. To this end, the expression of the genetic programme in plants is altered by the stress stimuli to induce and/or suppress the production of specific proteins which are either structural proteins or enzymes for specific metabolic pathways. 

In many Instances administered drugs alter a metabolic pathway and directly produce changes In biochemical values. 

Changes that follow the primary disorder and attempt to restore the blood pH to normal are referred to as compensatory changes. It should be stressed that compensation never normalizes the pH. Because all metabolic acid-base disorders are chronic and the normal respiratory system can quickly alter the PaC02, essentially all metabolic disorders are accompanied by some degree of respiratory compensation.3 Similarly, chronic respiratory acid-base disorders are typically accompanied by attempts at metabolic compensation.4,5 However, with acute respiratory acid-base disorders there is insufficient time for the metabolic pathways to compensate significantly.6 As such, acute respiratory derangements are essentially uncompensated. 

The first-pass effect has not been extensively evaluated in infants and children. The maturational rate of metabolic pathways would be directly related to the oral bioavailability of a drug subject to first-pass effect. Drugs that undergo glucuronidation during en-terohepatic recirculation may have altered systemic availability in children up to approximately 3 years of age because of delayed maturation of conjugation. 

The metabolic pathways of chloroform metabolites are well understood. It appears that both the mode of oral administration and the vehicle affect metabolism. Additional data investigating the mode and vehicle of administration would be useful in order to understand the role of these factors in the mechanism of chloroform s toxicity. The co-administration of other compounds (e.g., ethanol) has been shown to alter chloroform metabolism and toxicity. Further investigations of the hazards associated with exposure to complex mixtures containing chloroform would be useful. 

Fig. 10.6 Metabolic pathway between HMG-CoA reductase and cholesterol (altered by Lipitor).

Inhibition of metabolic pathway Sulfonamides Sulfamethoxazole Efflux Altered target... 

Development of altered metabolic pathways, which permits the effect of the drug to be bypassed. 

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