Metabolic inhibition

In the case of dmg interactions involving metabolic inhibition, little increase in the substrate concentration is expected when the inhibition constant (K ) determined in in vitro studies using human liver samples is larger than the inhibitor concentration in vivo. Various approaches have been adopted using mathematical models in attempts to quantitatively predict in vivo dmg interactions from in vitro data [5]. 

Irreversible metabolic inhibition caused by covalent binding of the inhibitor to the enzyme after being metabolized by the same enzyme. The inhibitory effect remains after elimination of the inhibitor from the body. 

Reversible metabolic inhibition caused by an inhibitor binding to an enzyme site different from the substrate. The degree of inhibition is independent of the substrate concentration. 

Transduction mechanism Inhibition of adenylyl cyclase stimulation of tyrosine phosphatase activity stimulation of MAP kinase activity activation of ERK inhibition of Ca2+ channel activation stimulation of Na+/H+ exchanger stimulation of AM PA/kainate glutamate channels Inhibition of forskol in-stimulated adenylyl cyclase activation of phos-phoinositide metabolism stimulation of tyrosine phosphatase activity inhibition of Ca2+ channel activation activation of K+ channel inhibition of AM PA/ kainate glutamate channels inhibition of MAP kinase activity inhibition of ERK stimulation of SHP-1 and SHP-2 Inhibition of adenylyl cyclase stimulation of phosphoinositide metabolism stimulation of tyrosine phosphatase activation of K+ channel inhibi-tion/stimulation of MAP kinase activity induction of p53 and Bax Inhibition of adenylyl cyclase stimulation of MAP kinase stimulation of p38 activation of tyrosine phosphatase stimulation of K+ channels and phospholipase A2 Inhibition of adenylyl cyclase activation/ inhibition of phosphoinositide metabolism inhibition of Ca2+ influx activation of K+ channels inhibition of MAP kinase stimulation of tyrosine phosphatase... 

Within the plant. Excessive concentrations of some ions occur in the tissue overall, in the cytoplasm, or in the apoplast. Effects include metabolic inhibition, interference with protein synthesis, cellular dehydration, stomatal closure and early senescence of leaves. Since both cytoplasm and apoplast are small compartments, imbalance between compartments may amplify the effects of excess salt, resulting in toxicity despite apparently moderate overall tissue concentrations. 

The reported (14) mechanisms of action of allelochemlcals Include effects on root ultrastructure and subsequent Inhibition of Ion absorption and water uptake, effects on hormone-induced growth, alteration of membrane permeability, changes In lipid and organic acid metabolism, inhibition of protein synthesis and alteration of enzyme activity, and effects on stomatal opening and on photosynthesis. Reduced leaf water potential Is one result of treatment with ferulic and p-coumaric acids (15). Colton and Einhellig (16) found that aqueous extracts of velvetleaf (Abutllon theophrastl Medic.) Increased diffusive resistance In soybean fGlycine max. (L.) Merr.] leaves, probably as a result of stomatal closure. In addition, there was evidence of water stress and reduced quantities of chlorophyll In Inhibited plants. 

Elahi, E.N., et al., Protein binding and metabolic inhibition reveals clues on the mechanisms surrounding relative potency of sensitising cinnamic compounds. Toxicology, 178, 43, 2002. 

Disulfiram (Antabuse). Disnlfiram is the only medication specifically approved by the FDA as an aversion therapy for snbstance abnse, specifically alcohol abnse or dependence. Disnlfiram s mechanism of action is qnite simple it is an inhibitor of alcohol dehydrogenase, the major enzyme responsible for the metabolism. Inhibiting this enzyme resnlts in the accnmnlation of acetylaldehyde. Acetylaldehyde is primarily responsible for many of the nnmistakable symptoms of a hangover, and when it accnmnlates in the presence of disnlfiram, it produces a constellation of very nncomfortable physical symptoms. 

When data are available to enable comparison of the plasma concentration time profile after single administration with that after repeated administration, this would enable determination of whether the substance has time dependent kinetics (due to induction of metabolism, inhibition of metabolism, and/or accumulation and saturation of processes involved in distribution, metabohsm, and excretion). 

Cytochrome P-450 Isoenzymes and Common Dru9S They Metabolize, Inhibit, and Induce ... 

Martignoni, M., Groothuis, G.M. and de Kanter, R. (2006) Species differences between mouse, rat, dog, monkey and human CYP-mediated drug metabolism, inhibition and induction. Expert Opinion on Drug Metabolism and Toxicology, 2, 875-894. 

Rash risk in 5%-10% Rarely, life-threatening rash (including Stevens-Johnson syndrome) Risk minimized by low starting dose and slow titration Metabolism inhibited by valproate Metabolism induced by carbamazepine... 

In contrast to anticonvulsants and alcohol, drugs such as bupropion, fluoxetine, fluvoxamine, nefazodone, quinidine, paroxetine, and some antipsychotics can inhibit specific CYP enzymes (7, 11, 36, 37, 41, 42, 43 and 44). Thus, TCAs, certain BZDs, bupropion, some steroids, and antipsychotics can all have their metabolism inhibited by drugs such as fluoxetine. For example, fluoxetine at 20 mg/day produces on average a 500% increase in the levels of coprescribed drugs which are principally dependent on CYP 2D6 for their clearance. That can lead to serious or even life-threatening toxicity if the drug has a narrow therapeutic index and the dose is not adjusted for the change in clearance caused by the coadministration of fluoxetine. 

SSRIs such as fluoxetine and paroxetine may inhibit the metabolism of antipsychotics, increasing their plasma levels and the chance for toxicity ( 517, 518). While antipsychotics may inhibit the metabolism of tricyclic antidepressants, or, in turn, have their metabolism inhibited by tricyclic antidepressants, the clinical relevance is uncertain. 

Hibbs, J. B., Vavrin, Z., and Taintor, R. R. (1987b). L-Arginine is required for expression of the activated macrophage effector mechanism causing selective metabolic inhibition in target cells.T Immunol. 138, 550-565. 

Methanol is a solvent, which is added to ethanol and sometimes used in antifreeze. The main target organ is the optic system resulting from metabolic inhibition and systemic toxicity due to metabolic acidosis from formate and lactate. Toxicity is due to metabolism to formic acid via alcohol dehydrogenase and insufficient detoxication via tetrahydrofolate. The overall result is circulus hypoxicus. Treatment involves blockade of metabolism with ethanol and treatment of metabolic acidosis (NaHCC>3). 

The results of these experiments are summarized briefly in Table II. The stimulation caused by adding both metabolic inhibitions on the unirradiated control tissue is not obtained with tissues receiving increasing... 

Sundstrom E. and Mo L. L. (2002). Mechanisms of glutamate release in the rat spinal cord slices during metabolic inhibition. J. Neurotrauma 19 257-266. 

---