Inhibitors nontoxic

Precipitation and Vapor-Phase Inhibitors. Precipitation inhibitors are film-forming compounds that produce barrier films over the entire surface. Phosphates and siUcates, which are the most common, do not provide the degree of protection afforded by chromate inhibitors, but are useful in situations where nontoxic additives are required. Two main drawbacks to the use of phosphates and siUcates are the dependence on the water composition and the control required to achieve maximum inhibition (37,38). 

Ethanol water is a solution of denatured grain alcohol. Its main advantage is that it is nontoxic and thus is widely used in the food and chemic industry. By using corrosion inhibitors it could be made non-corrosive for brine service. It is more expensive than methanol water and has somewhat lower heat transfer coefficients. As an alcohol derivate it is flammable. 

Salt solution is nontoxic and does not need replacement unless spilled but does require a corrosion inhibitor. 

Stirpe, F., Olsnes, S., and Pihl, A. (1980) Gelonin, a new inhibitor of protein synthesis, nontoxic to intact cells. Isolation, characterization, and preparation of cytotoxic complexes with concanavahin A./. Biol. Chem. 255, 6947-6953. 

The key to unraveling the toxicity of fluoracetate came from observations of Buffa and Peters (1949) that in animals treated with FAc, considerable quantities of citrate accumulated in some tissues. Oxygen uptake was also diminished. The citric acid cycle was thus implicated as the site of inhibition. Fluorcitrate was then isolated from the affected tissues. It was found to be a powerful competitive inhibitor of aconitase, thus blocking citrate oxidation. The suggestion was therefore made that fluoracetate was toxic not in itself, but because it was metabolized in cells via fluoracetyl CoA to give a toxic derivative, an example of lethal synthesis —the capacity of organisms to metabolize nontoxic compounds and convert them to potentially lethal products. 

Amidases can be found in all kinds of organisms, including insects and plants [24], The distinct activities of these enzymes in different organisms can be exploited for the development of selective insecticides and herbicides that exhibit minimal toxicity for mammals. Thus, the low toxicity in mammals of the malathion derivative dimethoate (4.44) can be attributed to a specific metabolic route that transforms this compound into the nontoxic acid (4.45) [25-27]. However, there are cases in which toxicity is not species-selective. Indeed, in the preparation of these organophosphates, some contaminants that are inhibitors of mammalian carboxylesterase/am-idase may be present [28]. Sometimes the compound itself, and not simply one of its impurities, is toxic. For example, an insecticide such as phos-phamidon (4.46) cannot be detoxified by deamination since it is an amidase inhibitor [24],... 

It is very likely that the inhibitors are breakdown products of glucosinolates, which are considered nontoxic in themselves (23) but can yield physiologically active products upon hydrolysis by the enzyme myrosinase. Through hydrolysis glucosinolates can yield isothiocyanates (24-28). Ju et al. (29) demonstrated the capacity of thiocyanates as allelopathic agents, and isothiocyanates also have allelopathic activity (30). 

Selective bioactivation (toxification) is illustrated in the case of the insecticide malathion (3.35). This acetylcholinesterase inhibitor is desulfurized selectively to the toxic malaoxon, but only by insect and not mammalian enzymes. Malathion is therefore relatively nontoxic to mammals (LDjg = 1500 mg/kg, rat p.o.). Higher organisms rapidly detoxify malathion by hydrolyzing one of its ester groups to the inactive acid, a process not readily available to insects. This makes the compound doubly toxic to insects since they cannot eliminate the active metabolite. 

Preclinical and clinical results indicate that both entacapone and tolcapone are orally active, nontoxic and well-tolerated drugs. The adjuvant L- dopa therapy with DDC inhibitor + COMT-inhibitor (+ possible MAO inhibitor) may substitute for the present double therapy in the treatment of Parkinson s disease [27-40]. Together with the development of dopamine agonists and MAO inhibitors, the inhibition of COMT will constitute major progress in the treatment of Parkinson s disease in the near future. 

Among the most deadly of simple compounds is sodium fluoroacetate. The LD50 (the dose lethal for 50% of animals receiving it) is only 0.2 mg/kg for rats, over tenfold less than that of the nerve poison diisopropylphosphofluoridate (Chapter 12).a b Popular, but controversial, as the rodent poison "1080," fluoroacetate is also found in the leaves of several poisonous plants in Africa, Australia, and South America. Surprisingly, difluoroacetate HCF2-COO is nontoxic and biochemical studies reveal that monofluoroacetate has no toxic effect on cells until it is converted metabolically in a "lethal synthesis" to 2R,3R-2-fluorocitrate, which is a competitive inhibitor of aconitase (aconitate hydratase, Eq. 13-17).b This fact was difficult to understand since citrate formed by the reaction of fluorooxalo-acetate and acetyl-CoA has only weak inhibitory activity toward the same enzyme. Yet, it is the fluorocitrate formed from fluorooxaloacetate that contains a fluorine atom at a site that is attacked by aconitase in the citric acid cycle. 

Inhibition of these prenyltransferases blocks growth of tumor cells. Many prenyltransferase inhibitors are apparently nontoxic to normal cells and are undergoing human clinical trials as anticancer drugs.763 79a b Among other important polyprenyl... 

Notes aHighest nontoxic concentration of inhibitor in cultured NIH 3T3 cells as determined by viable staining with MTT. 

Reports that colchicine showed promising activity as an inhibitor of human immunodeficiency virus (HIV) replication (133,134) initiated the synthesis of derivatives of colchicine and thiocolchicine as potential inhibitors of HIV replication in H9 lymphocytic cells (135). Colchicine was found to be slightly active at nontoxic doses. All the other compounds, which were found inactive in this assay, were derivatives of colchiceine and/or A/-deacetylcolchicine. It is well established that both of these structural changes reduce dramatically binding to tubulin, and the reported results are, therefore, not completely surprising. 

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