Respiratory uncoupler

Cajina-Quezada, M. and Schultz, T.W. (1990) Structure - toxicity relationships for selected weak acid respiratory uncouplers, Aquatic Toxicology 17, 239-252. 

DeSantis P, Coleman T, Townsend RR, Muglia LJ, Semenkovich 204. CF. Vascular respiratory uncoupling increases blood pressure and atherosclerosis. Nature 2006 435 502-506. 

The mechanism of toxic action involved in the algorithm loop of Fig. 4 is associated with the critical biological effect of the toxicant at the molecular or cellular level. The main classes of toxic action mechanisms are as follows nonpolar narcosis, polar narcosis, weak acid respiratory uncoupling, formation of free radicals, electrophilic reactions, and toxic action by specific (receptor-mediated) mechanisms. 

In order to reveal the mechanisms for the toxicity of heavy metals, pathological and biochemical analyses of the tissues are required. In addition, analyses of swimming behaviors of test fish are also helpful to inspect how the toxicity of heavy metals is expressed. Drummond [10] analyzed swimming ability, respmise to stimuli, and respiration patterns of fathead minnows, and classified the action of toxic substances into four groups narcosis, respiratory uncoupler, respiration irritant, and acetylcholinesterase inhibitor [10]. He did not analyze heavy metals, but the methods of his analyses are possibly applicable for evaluating the mode of action of heavy metals. 

The protonophore mechanism of respiratory uncoupling has been questioned on the basis of results obtained with the use of affinity-labeled uncouplers " (see Ref. 5). Such studies have led to a proposal of an uncoupling binding site associated with ATPase. " ... 

Refs. 125 and 127). However, although 3- and 4-hydroxyl-dichlobenil are significant metabolites in plants, they are likely to be readily conjugated, and the respiratory uncoupling can be considered a secondary site of action. 

Inhibition of protein, RNA, and DNA synthesis by herbicides has been the subject of numerous reports and reviews (see, e.g.. Refs. 3, 4, and 137-139). Inhibition of the biosynthesis of any of these macromolecules would lead to an effective and abrupt cessation of plant growth. However, with very few exceptions, the reports on herbicidal interference with protein and nucleic acid synthesis reflect secondary effects resulting from an effect at a target site elsewhere in the cell. For example, any interruption of the production of metabolic energy, as a result of respiratory uncoupling and/or inhibition, would lead to a rapid cessation of macromolecular synthesis. In several surveys of herbicide effects on C-labeled precursor incorporation into protein and RNA in excised plant tissues and isolated mesophyll cells, dinitrophenols and hydroxybenzonitriles were the most potent inhibitors (Section 5.1 see, e.g.. Refs. 138 and 140). 

The second experiment we present in this tutorial for classifying compounds according to their mechanism of action involves the classifications of 88 chemicals. The chemicals are either narcotics (nonpolar and polar narcotics) and reactive compounds (respiratory uncouplers, soft electrophiles, and proelectrophiles).The dataset, consisting of 48 narcotic compounds... 

In the first test we used SVM models to discriminate between nonpolar narcotic compounds (chemicals that have baseline toxicity) and other com-potmds having excess toxicity (representing the following MO As polar narcotics, ester narcotics, amine narcotics, weak acid respiratory uncouplers, electrophiles, proelectrophiles, and nucleophiles). From the total set of 337 compotmds, 126 represent the SVM class -Fl (nonpolar narcotic) and 211 represent the SVM class —1 (all other MOA classes). 

The adipocytes used as the test system for mammalian cells were grown in 96-well plates with the well-known respiratory uncoupler, carbonyl cyanide p-(trifluoromethoxy)phenylhydrazone (FCCP) or the inhibitor of the respiratory chain, rotenone. The results reproduced in Figure 47 validated the analytical... 

Weak acid respiratory uncouples Phenols and anilines with four or more halogen substituent or more than one nitro group, or single nitro group and more than one halogen group... 

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