Inhibition mitochondrial electron transport

As in the xenognosins, the presence of at least one methoxy functionality appears to be of critical Importance. All three Isomeric dimethoxyquinones fulfill this requirement, but only 2,3-DMBQ (6) and 2,6-DMBQ (4) induce haustoria. Both compounds have been shown to inhibit mitochondrial electron transport (25,26). In contrast, the 2,5-isomer (5) shows no such inhibition of respiration and does not induce haustoria. A possible connection between the inhibition of electron transport and the haustoria-inducing activity of these quinones has yet to be clarified. 

Atovaquone compounds that inhibit mitochondrial electron transport in the parasite... 

Figure 7.44 The metabolism and toxicity of MPTP. Diffusion into the brain is followed by metabolism in the astrocyte. The metabolite MPP+ is actively transported into the dopaminergic neuron by DAT. It is accumulated there and is actively taken into mitochondria by another uptake system. Here, it inhibits mitochondrial electron transport between NADH dehydrogenase (NADH DHase) and coenzyme Q (Q10). Consequently, it blocks the electron transport system, depletes ATP, and destroys the neuron. Abbreviations MPTP, 1-methyl-4-phenyl 1,2,3,6-tetrahydropyridine DAT, dopamine transporter uptake system.

Derris. An insecticide of plant origin. Can be used as a fish poison. Oral nausea and vomiting. Chronic exposure liver and kidney damage. Massive exposure respiratory paralysis and death. By inhalation intense respiratory stimulation and then depression, convulsions, death. Inhibits mitochondrial electron transport. 

FIGURE 7.30 The metabolic activation and proposed mechanism of toxicity of MPTP in the central nervous system. Thus MPP+ is actively taken into the neurone where it inhibits mitochondrial electron transport between NADH dehydrogenase (NADH DHase) and coenzyme Q (Qiq). MPTP l-Methyl-4-... 

Piericidin Ai (37) has been isolated from Streplomyces sp., including S. mobaraensis and S. pactum [140,142], A potent insecticide [140], piericidin A inhibits mitochondrial electron transport through its action on NADH-ubiquinone reductase [146]. 

Atovaquone is an antiprolozoal agent (750 mg p.o. t.i.d for 21 days), that inhibits mitochondrial electron transport in metabohc enzymes of microorganisms. This may cause inhibition of nucleic acid and adenosine triphosphate synthesis. Atovaquone is indicated in the treatment of mild to moderate Pneumocystis carinii pneumonia in patients who cannot tolerate trimethoprimsulfamethoxazole, and in acute oral treatment of mild to moderate PCP in patients who are intolerant to trimethoprimsulfamethoxazole. 

Atovaquone is an antimalarial preparation. It inhibits mitochondrial electron transport in parasites, causing inhibition of nucleic acid synthesis. Proguanil exerts its effect by means of the metabolite cycloguanil, which inhibits dihydrofolate reductase in the malarial parasite, disrupting deox-ythymidylate synthesis. It is indicated in prophylaxis of P. falciparum in patients with severe renal impairment (Ccr less than 30 mL/min) hypersensitivity to any component of the product. 

Mechanism and pharmacokinetics Atovaquone inhibits mitochondrial electron transport and probably folate metabolism. Used orally, it is poorly absorbed and should be given with food to maximize bioavailability. Most of the drug is eliminated in the feces in unchanged form. 

Mechanisms Etoposide increases degradation of DNA, possibly via interaction with topoisomerase II, and also inhibits mitochondrial electron transport. TTie drug is most active in the late S and early G2 phases of the cell cycle. Teniposide is an analog with very similar pharmacologic characteristics. 

The electron transport inhibitors do not directly affect photophosphorylation or interfere with mitochondrial electron transport and phosphorylation ( 1), However, the inhibitory uncouplers, in addition to interfering with electron transport in thylakoids, uncouple photophosphorylation and oxidative phosphorylation, and inhibit mitochondrial electron transport. 

Mitochondrial Responses. The herbicides referred to as inhibitory uncouplers were so named because at low molar concentrations they satisfy most, if not all, of the criteria established for uncouplers of oxidative phosphorylation. However, at higher molar concentrations, they also inhibit mitochondrial electron transport ( 1). ... 

Fluacrypyrim (73 2002, Titaron , Nippon Soda) [118] is the first strobilurin analogue to be marketed as an acaricide rather than a fungicide - it inhibits mitochondrial electron transport at complex III of the respiratory chain. It is active against all growth stages of spider mites and shows an acaricidal contact and... 

Hydramethylnon [67485-29-4] is tetrabydro-5,5-dimetbyl-2-(1 H)-pyrimidinone [bis-l,5-(4-trifluoromethylphenyl)-3-penta-l,4-dienylidene] hydrazone (152) (mp 189°C). It is a slow-acting stomach poison used in baits and traps to control ants and cockroaches. Its mode of action is inhibition of mitochondrial electron transport. 

When induced in macrophages, iNOS produces large amounts of NO which represents a major cytotoxic principle of those cells. Due to its affinity to protein-bound iron, NO can inhibit a number of key enzymes that contain iron in their catalytic centers. These include ribonucleotide reductase (rate-limiting in DNA replication), iron-sulfur cluster-dependent enzymes (complex I and II) involved in mitochondrial electron transport and cis-aconitase in the citric acid cycle. In addition, higher concentrations of NO,... 

Much progress has been made in understanding the different mechanisms that can cause mitochondrial dysfunction, such as (i) uncoupling of electron transport from ATP synthesis by undermining integrity of inner membrane (ii) direct inhibition of electron transport system components (iii) opening of the mitochondrial permeability transition pore leading to irreversible collapse of the transmembrane potential and release of pro-apoptotic factors (iv) inhibition of the... 

Atovaquone is a hydroxy-1,4-naphthoquinone, an analog of ubiquinone, with antipneumocystic activity. Since 2000 atovaquone is available as a fixed dose preparation (Malarone) with proguanil for the oral treatment of falciperum malaria. Its activity probably is based on a selective inhibiton of mitochondrial electron transport with consequent inhibition of pyrimidin synthesis. Malarone should not be used to treat severe malaria, when an injectable drug is needed. 

Atovaquone is a naphthoquinone whose mechanism of action involves inhibition of the mitochondrial electron transport system in the protozoa. Malaria parasites depend on de novo pyrimidine biosynthesis through dihy-droorotate dehydrogenase coupled to electron transport. Plasmodia are unable to salvage and recycle pyrimidines as do mammalian cells. 

Mechanism of Action A systemic anti-infective that inhibits the mitochondrial electron-transport system at the cytochrome bcl complex (Complex 111), which interrupts nucleic acid and adenosine triphosphate synthesis. Therapeutic Effect Antiprotozoal and antipneumocystic activity. 

Radi, R., Rodriguez, M., Castro, L., and Telleri, R. (1994). Inhibition of mitochondrial electron transport by peroxynitrite. Arch. Biochem. Biophys. 308, 89-95. 

Granger, D. L., and Lehninger, A. L. (1982). Sites of inhibition of mitochondrial electron transport in macrophage-injured neoplastic cells. J. Cell Biol. 95, 521-535. 

Treatment of isolated hepatocytes with authentic nitric oxide inhibits the electron transport chain at complexes I and II, and mitochondrial aconitase activity (Stadler et al., 1991). 

Recently introduced insecticide/acaricides, pyrimidifen and fenaza-quin (Figure 3.13), also inhibit the mitochondrial electron transport chain by binding with complex I at coenzyme site Q. 

Depletion of ATP is caused by many toxic compounds, and this will result in a variety of biochemical changes. Although there are many ways for toxic compounds to cause a depletion of ATP in the cell, interference with mitochondrial oxidative phosphorylation is perhaps the most common. Thus, compounds, such as 2,4-dinitrophenol, which uncouple the production of ATP from the electron transport chain, will cause such an effect, but will also cause inhibition of electron transport or depletion of NADH. Excessive use of ATP or sequestration are other mechanisms, the latter being more fully described in relation to ethionine toxicity in chapter 7. Also, DNA damage, which causes the activation of poly(ADP-ribose) polymerase (PARP), may lead to ATP depletion (see below). A lack of ATP in the cell means that active transport into, out of, and within the cell is compromised or halted, with the result that the concentration of ions such as Na+, K+, and Ca2+ in particular compartments will change. Also, various synthetic biochemical processes such as protein synthesis, gluconeogenesis, and lipid synthesis will tend to be decreased. At the tissue level, this may mean that hepatocytes do not produce bile efficiently and proximal tubules do not actively reabsorb essential amino acids and glucose. 

Decreased metabolism of lipids. Decreased mitochondrial oxidation of fatty acids is another possible cause of ethanol-induced steatosis. Other possible causes are vitamin deficiencies and the inhibition of the mitochondrial electron transport chain. 

MPTP is a molecule, which is sufficiently lipophilic to cross the blood-brain barrier and enter the astrocyte cells. Once in these cells, it can be metabolized by monoamine oxidase B to MPDP and then MPP both of which are charged molecules. These metabolites are therefore not able to diffuse out of the astrocyte into the bloodstream and away from the brain. However, the structure of MPP allows it to be taken up by a carrier system and concentrated in dopaminergic neurones. In the neurone, it inhibits the mitochondrial electron transport chain leading to damage to the neurone. 

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