Nonspecific inhibition

Poirier MC, DeCicco BT, Lieberman MW. 1975. Nonspecific inhibition of DNA repair synthesis by tumor promotors in human diploid fibroblasts damage with N-acetoxy-2-acetylaminofluorene. Cancer Res 35 1392-1397. 

R. Zaydan, M. Dion and M. Boujtita, Development of a new method, based on a bioreactor coupled with an L-lactate biosensor, toward the determination of a nonspecific inhibition of L-lactic acid production during milk fermentation, J. Agric. Food Chem., 52(1) (2004) 8-14. 

A natural SP OKU-40 was extracted from the marine microalga Dinoflag-ellata and was found to inhibit the replication of HIV, RSV, influenza A and B viruses, measles virus, and parainfluenza viruses type 2 (PIV-2). However, it did not inhibit the replication of mumps virus or PIV-3 [98]. The action of negatively charged polysaccharides is not merely one of nonspecific inhibition of the binding of an enveloped virus to receptors. In fact, OKU-40 did not inhibit the binding of HIV or influenza A virus to the cell membrane, but it did inhibit the fusion of the membranes of HIV-infected MOLT-4 cells to those of uninfected cells and the fusion of the influenza A virus envelope to uninfected MDCK cells [99]. 

As important as validation studies for synthetic samples are in running a successful discovery program, they are even more important for running natural product samples and especially plant extracts, which are notoriously difficult to run in biochemical or enzyme-based screens. Tannins in particular are responsible for nonspecifically inhibiting activities in such screens. Other nuisance compounds include chlorophyll, melanin, lipids, and waxes. 

McGovern SL, Helfand BT, Feng B, Shoichet BK (2003) A specific mechanism of nonspecific inhibition. J Med Chem 46 4265-4272... 

Rat liver microsomes also catalyzed benzo[a]pyrene metabolism in cumene hydroperoxide (CHP)-dependent reactions which ultimately produced 3-hydroxybenzo[a]pyrene and benzo[a]pyrene-quinones (Cavalieri et al. 1987). At low CHP concentrations, 3-hydroxybenzo[a]pyrene was the major metabolite. As CHP concentrations increased, levels of quinones increased and levels of 3- hydroxybenzo[a]pyrene decreased. This effect of varying CHP levels was reversed by preincubating with pyrene. Pyrene inhibited quinone production and increased 3-hydroxybenzo[a]pyrene production. Pretreatment with other PAHs like naphthalene, phenanthrene, and benz[a]anthracene nonspecifically inhibited the overall metabolism. The binding of benzo[a]pyrene to microsomal proteins correlated with quinone formation. This suggested that a reactive intermediate was a common precursor. The effects of pyrene on benzo[a]pyrene metabolism indicated that two distinct microsomal binding sites were responsible for the formation of 3-hydroxybenzo[a]pyrene and benzo[a]pyrene-quinone (Cavalieri et al. 1987). 

The increase of conversion with rising concentration results from an increase of equilibrium conversion as depicted in Fig. 7-7. The decrease of conversion at ManNAc concentrations >500 mmol L 1 is due to the increasing effect of nonspecific inhibition (compare to Eq. (66)). The space-time yield decreases when the decrease of conversion exceeds the increase of ManNAc-concentration. 

The fungicidal effect of copper compounds can be attributed to the complexforming reactions of the copper(II) ions that penetrate the cell with the thiol or amino groups of the fungus, resulting in nonspecific inhibition of enzymes and denaturation of proteins of the fungus (Somers, 1961). 

Aromatic L-amino acid decarboxylase Widespread sympathetic nerves Cytoplasmic Pyiidoxal phosphate Nonspecific Inhibition does not alter tissue NE and Epi appreciably... 

Dopamine /3-hydroxylase Widespread sympathetic nerves Synaptic vesicles Ascorbic add, (contains copper) Nonspecific Inhibition can decrease NE and Epi levels... 

Phenylethanolamine iV-methyltransferase Largely in adrenal gland Cytoplasmic S -Adenosyl methionine (CH3 donor) Nonspecific Inhibition leads to decrease in adrenal catecholamines under control of glucocorticoids... 

Young S], Hart JP, Dowman AA et al. The nonspecific inhibition of enzymes by environmental pollutants A study of a model system towards the development of electrochemical biosensor arrays. Biosens Bioelectron 2001 16 887-894. 

Theophylline was initially classified as a bronchodilator nonspecific inhibition of phosphodiesterase isoenzymes was thought to be its major mechanism of action. It can, for example, completely block exercise-induced bronchospasms at concentrations in the npper therapentic range. Because phosphodiesterase inhibition by theophylline is only about 20% with clinical concentrations, however, involvement of other mechanisms of action is highly likely. The only other known molecular mechanism of theophylline at clinically relevant concentrations is a nonselective antagonism of specific cell-surface receptors for adenosine. 

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