Inhibition of oxidative phosphorylation

More recently, a new class of insecticides derived from naphthoquinones found in the South American alpine plant Calceolaria andina has entered development. Compounds are being developed jointly through the British Technology Group (BTG) (following the discovery at Rothamsted Experimental Station) and by Bayer. The mode of action of these compounds is believed to be an inhibition of respiration at site 

It is interesting that a new group of fungicides based on the natural products from the fungus Strobilurus tenacellus also inhibit mitochondrial respiration at the site of complex III (bei-complex) of the respiratory chain (see Chapter 4). Recently synthesised compounds from within this class are showing interesting insecticidal effects. 

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Intact tobacco plants were exposed to 0.60-0.70 yl/1 ozone for 1 hr mitochondria isolated from visibly injured tissue demonstrated an inhibition of oxidative phosphorylation in conjunction with an increase in respiration (6). However, when detached tobacco leaves were fumigated with 1.0 yl/1 ozone for 1-5 hr, the mitochondria extracted from the tissue prior to s3rmptom development exhibited reduced oxygen uptake and reduced oxidative phosphorylation (7 ). In an experiment of similar design when ozone was bubbled through a solution of isolated mitochondria, both respiration and oxidative phosphorylation were reduced (7 ). 

Niclosamide is a salicylamide derivative. Its mechanism of action could be based on inhibition of oxidative phosphorylation or on its ATPase stimulating action. The scolices and segments, but not segments of the ova, are rapidly killed. Niclosamide is minimally absorbed from the gastrointestinal tract and excreted, mostly unchanged, in the faeces. It is generally well tolerated with occasional gastrointestinal disturbances. Skin eruptions have been reported. 

Adult worms (but not ova) are rapidly killed, presumably due to inhibition of oxidative phosphorylation or stimulation of ATPase activity. 

Tin-containing compounds have been used in agriculture for many years as both fungicides (Chapter 4) and as acaricides. Tricyclohexyltin hydroxide and several related compounds (Figure 3.20), are very active against adult spider mites and are believed to act through an inhibition of oxidative phosphorylation. 

The mechanism of toxicity of ethylene glycol involves metabolism, but unlike previous examples, this does not involve metabolic activation to a reactive metabolite. Thus, ethylene glycol is metabolized by several oxidation steps eventually to yield oxalic acid (Fig. 7.84). The first step is catalyzed by the enzyme alcohol dehydrogenase, and herein lies the key to treatment of poisoning. The result of each of the metabolic steps is the production of NADH. The imbalance in the level of this in the body is adjusted by oxidation to NAD coupled to the production of lactate. There is thus an increase in the level of lactate, and lactic acidosis may result. Also, the intermediate metabolites of ethylene glycol have metabolic effects such as the inhibition of oxidative phosphorylation, glucose metabolism, Krebs cycle, protein synthesis, RNA synthesis, and DNA replication. 

Diphtheria toxin, inorganic lead, and tellurium are considered toxicants that cause demyelination through injury to the myelinating cell. The mechanism of action of diphtheria toxin was discussed in Section 30.1. The mechanism by which inorganic lead causes Schwann cell injury and demyelination is not well understood, but may be related to uncoupling or inhibition of oxidative phosphorylation secondary to interference of lead with some aspect of ion transport across the mitochondrial membrane. 

Pentamidine, an aromatic diamine, has been known since the late 1930s as a treatment for trypanosomiasis and some forms of leishmaniasis. In recent times it has been extensively used in the treatment of Pneumocystis jiroveci pneumonia. Its mechanism of action is probably related to inhibition of dihydrofolate reductase and inhibition of oxidative phosphorylation and nucleic acid synthesis, as well as an effect on aerobic glycolysis. 

As is the case with sorbic acid, benzoic acid penetrates the cell wall in the undissociated form. As a consequence, it is active at lower pH values only (pKa at 25°C = 4.19) and therefore serves as a preservative for sour products such as fruit juices and jams. In shrimp preservation it is applied as a powder that is spread over the shrimps, passes cell walls, and then ionizes in the intracellular fluid to yield protons that acidify the alkaline interior of the cell. The main cause of its activity, however, is biochemical effects (Eklund, 1980) such as inhibition of oxidative phosphorylation and of enzymes from the citric acid cycle (Chipley, 1983). In mayonnaise preserved by benzoic acid, the undissociated acid is mainly present in the lipid phase, which can be considered as a reservoir for the aqueous phase. 

Inhibition of oxidative phosphorylation by cyanide ion leads to increases in which of the following ... 

Gavin CE, Gunter KK, Gunter TE. 1992. Mrf" sequestrahon by mitochondria and inhibition of oxidative phosphorylation. Toxicol Appl Pharmacol 115 1-5. 

The general biological action of organic tin compounds is the inhibition of oxidative phosphorylation in the mitochondria, that is, the blocking of the incorporation of phosphoric acid into adenosine diphosphate in resulting in adenosine triphosphate of high energy content (Stockdale et al., 1970). 

Ioxynil and bromoxynil are photosynthesis inhibiting herbicides. They inhibit the electron flow near the quinone component of electron transport (Wain, 1964 Smith et al., 1966 Paton and Smith, 1965,1967). In addition to the strong inhibition of oxidative phosphorylation, both herbicides prevent COj fixation (Friend and Olson, 1967). 

GSH-peroxidase because of detoxification of putatively increased amounts of hydroperoxides. Therefore, it seems crucial to protect cells from loss of antioxidants and potent reducing substances, such as NADPH or NADH. In turn, depletion of cells from ATP by inhibition of oxidative phosphorylation could result in decreased activity of 5-oxoprolinase, glutamyl-cysteine-synthetase and GSH synthetase, all known to be dependent on ATP (Meister, 1991), resulting in impaired detoxification mechanisms and subsequent cell damage because of oxidative stress. 

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