Inhibitors of Oxidative Phosphorylation

Cyhexatin [13121 -70-5], tricyclohexylhydroxystannane (147) (mp 195°C), rat oral 540 mg/kg, and fenbutatin oxide [13356-08-6], hexakis-(2-methyl-2-phenylpropyl)distannoxane (148) (mp 138°C), rat oral LD q 2630 mg/kg, are two novel tin acaricides used on deciduous fmits. They are inhibitors of oxidative phosphorylation. 

Mechanistic studies have shown that TBT and certain other forms of trialkyltin have two distinct modes of toxic action in vertebrates. On the one hand they act as inhibitors of oxidative phosphorylation in mitochondria (Aldridge and Street 1964). Inhibition is associated with repression of ATP synthesis, disturbance of ion transport across the mitochondrial membrane, and swelling of the membrane. Oxidative phosphorylation is a vital process in animals and plants, and so trialkyltin compounds act as wide-ranging biocides. Another mode of action involves the inhibition of forms of cytochrome P450, which was referred to earlier in connection with metabolism. This has been demonstrated in mammals, aquatic invertebrates and fish (Morcillo et al. 2004, Oberdorster 2002). TBTO has been shown to inhibit P450 activity in cells from various tissues of mammals, including liver, kidney, and small intestine mucosa, both in vivo and in vitro (Rosenberg and Drummond 1983, Environmental Health Criteria 116). 

Much information about the respiratory chain has been obtained by the use of inhibitors, and, conversely, this has provided knowledge about the mechanism of action of several poisons (Figure 12-7). They may be classified as inhibitors of the respiratory chain, inhibitors of oxidative phosphorylation, and uncouplers of oxidative phosphorylation. 

Effects of Valinomycin on Oxidative Phosphorylation When the antibiotic valinomycin is added to actively respiring mitochondria, several things happen the yield of ATP decreases, the rate of 02 consumption increases, heat is released, and the pH gradient across the inner mitochondrial membrane increases. Does valinomycin act as an uncoupler or an inhibitor of oxidative phosphorylation Explain the experimental observations in terms of the antibiotic s ability to transfer K+ ions across the inner mitochondrial membrane. 

There is evidence that long-term phosphine exposure by individuals involved in the application of pesticides resulted in chromosome damage. Chronic exposure to very low levels of phosphine may result in altered motor, visual, and speech skills. Neither aluminum phosphide nor phosphine gas exhibit carcinogenicity in humans, or result in reproductive or developmental effects. Although definitive evidence is lacking, it is assumed that phospine is an in vivo inhibitor of oxidative phosphorylation. 

Hilton J, Walker M. 1977. DNA strand scission and its repair following exposure of cells to inhibitors of oxidative phosphorylation. Biochem Biophys Res Commun 75 909-914. 

Otigomycin B, C H Oy, 28-oxootigomycin A. Potent inhibitor of oxidative phosphorylation Lardy et ol. Arch. Biochem. Biophys. 78, 587 (1958). 

OH-D3-24-hydroxylase has also been demonstrated to occur in the kidney but not exclusively so This enzyme also hydroxyUtes 1,25-(0H)2D3 to form 1.24R,25-(OH)3D3 A 244iydroxylase has also been located in intestine which apparently is more specific for l,25-(OH)2D3 Another 24-hydroxylase has been reported in cartilage tissue The chick kidney reaction occurs in the mitochondria and in general is similar to the 25-OH-D3-la-hydroxy-lase In intact mitochondria it is supported by Krebs cycle substrates, utilizes molecular oxygen and is blocked by inhibitors of oxidative phosphorylation. In calcium swollen mitochondria, NADPH will support the reaction and under these circumstances the reaction is independent of the electron transport stem and oxidation phosphorylation. However, this reaction is not carbon monoxide sensitive and does not appear to be dependent upon cytochrome P-450. It is, however, a mbced-function monooxygenase as demonstrated by 02 experiments It is induced by 1,25-(OH)2D3 and is absent in vitamin D-deficient tissue Its substrate specificity is similar to that of the 25-OH-D3-la-hydroxylase. It has not been further studied nor has it been successfully solubilized at the present time. 

Inhibitors of oxidative phosphorylation, disrupters of ATP formation (inhibitors of ATP synthase) 12A Diafenthiuron 12B Organotin miticides 12C Propargite Tetradifon Diafenthiuron Azoqfdotin, Cyhexatin, Fenbutatin oxide Propargite Tetradifon... 

Inhibitors of Oxidative Phosphorylation via Disruption of the Proton Gradient 879... 

Rotenoids are effective inhibitors of oxidative phosphorylation in animal mitochondria this effect is responsible for the insecticidal properties of this group of compounds (Williams and Harbome, 1989b). This effect may occur at concentrations as low as 24 nmol/g of mitochondrial tissue. The lethal dose of rotenone in the silkworm is 0.003 mg/g body weight (Harbome, 1991). This series of compounds also inhibits other enzymes (McClure, 1975). 

In the meantime, this control of initiation has taken on greater significance by the finding that initiation is reversibly inhibited under a very wide variety of conditions (see references 20, 21, 23) in the absence of added haemin in the presence of low concentrations of double-stranded RNA (dsRNA) when oxidised glutathione is added at high temperatures (42-44 ) when the lysate has been subjected to high hydrostatic pressures when the lysate has been prepared from cells subjected to ATP depletion by incubation under anaerobic conditions or with inhibitors of oxidative phosphorylation (24, 25) when the lysate is depleted of low molecular weight compounds by gel-filtration. 

Dinitrophenol is an inhibitor of oxidative phosphorylation. Mitochondria isolated from the lungs of rats kept at 85 2% O2 for 7 days, when treated with 0.5 mM 2,4-dinitrophenol, in the presence of 1 mM CN" were maximally uncoupled, since state 3U respiration in the presence of 2,4-dinitrophenol was identical to the mitochondria oxygen consumption measured after ADP addition when 2,4-dinitrophenol was absent (Freeman and Crapo 1981). 

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