Inhibition mitochondrial oxidative

The lower trialky Itin compounds are able to inhibit mitochondrial, oxidative phosphorylation (471,477) and, therefore, disrupt the funda-... 

Biguanides such as metformin are thought to inhibit mitochondrial oxidation of lactic acid, thereby increasing the chance of lactic acidosis occurring. Fortunately, the incidence of lactic acidosis in clinical practice is rare. Patients at greatest risk for developing lactic acidosis include those with liver disease or heavy alcohol use, severe infection, heart failure, and shock. Thus, it is common practice to evaluate liver function prior to initiation of metformin. 

In a chemical model for oxidative phosphorylation77 the anaerobic oxidation of iV-benzyl 1,4-dihydronicotinamide by a pyridine solution of haemin was accompanied by the synthesis of ATP from ADP and inorganic phosphate. In support of an alternative chemical model involving sulphenyl phosphates as the reactive species,78 lipophilic thioureas have been shown to inhibit mitochondrial oxidative phos-... 

Partial reactions not dependent on photosystem II, such as cyclic phosphorylation or the photoreduction of NADP with an electron donor that circumvents photosystem II (ascorbate + DPIP), are either not inhibited or inhibited only weakly. These herbicides also do not inhibit mitochondrial oxidative phosphorylation. 

All organic tin compounds inhibit mitochondrial oxidative phosphorylation (hydrolysis of adenine triphosphate) and brain glucose oxidation and are toxic. Very little data are available on inorganic tin. 

Good selectivity is shown by a soil fungicide, sodium / -dimethylamino-benzenediazosulfonate ( Dexon ), which inhibits mitochondrial oxidation of NADH in the fungus Pythium ultimum. Sugar beets, which this fungus infects, have an enzyme in the mitochondria which decomposes this fungicide (Tolmsoff, 1962). 

A study of the in vitro effects of piperine on three bioenergetic reactimis, namely, oxidative phosphorylation, ATPase activity, and calcium transport by isolated rat liver mitochondria, suggested that piperine inhibits mitochondrial oxidative phosphorylation at the level of respiratory chain [87]. Piperine did not inhibit the mitochondrial ATPase activity induced by dinitrophenol and was found to diminish calcium uptake. The influence of piperine on the enzymes and bioenergetic functions in isolated rat hver mitochondria and hepatocytes has been studied, and it was observed that piperine produces concentration-related site-specific effects on mitochondrial bioenergetics and enzymes of energy metabolism [88]. 

The effects of variations in the fatty acid composition of membranes on the function of membrane-bound enzymes have been investigated in limited instances, under physiological conditions. For example, with mutant Saccharomyces cerevisiae species which cannot synthesize unsaturated fatty acids, depletion of unsaturated fatty acids inhibits mitochondrial oxidative phosphorylation (Haslam, 1971). This does not result from decreased synthesis or activity of any mitochondrial enzyme but represents an uncoupling between substrate and NAD/NADFl metabolism and the ability to synthesize ATP. It is also of interest that the morphology of Mycoplasma laidlawii is susceptible to variation as a function of the fatty acid composition of its membranes (Steim et al., 1969). 

Insects poisoned with rotenone exhibit a steady decline ia oxygen consumption and the iasecticide has been shown to have a specific action ia interfering with the electron transport iavolved ia the oxidation of reduced nicotinamide adenine dinucleotide (NADH) to nicotinamide adenine dinucleotide (NAD) by cytochrome b. Poisoning, therefore, inhibits the mitochondrial oxidation of Krebs-cycle iatermediates which is catalysed by NAD. 

The rate of mitochondrial oxidations and ATP synthesis is continually adjusted to the needs of the cell (see reviews by Brand and Murphy 1987 Brown, 1992). Physical activity and the nutritional and endocrine states determine which substrates are oxidized by skeletal muscle. Insulin increases the utilization of glucose by promoting its uptake by muscle and by decreasing the availability of free long-chain fatty acids, and of acetoacetate and 3-hydroxybutyrate formed by fatty acid oxidation in the liver, secondary to decreased lipolysis in adipose tissue. Product inhibition of pyruvate dehydrogenase by NADH and acetyl-CoA formed by fatty acid oxidation decreases glucose oxidation in muscle. 

Hydrogen sulfide inhibits mitochondrial cytochrome oxidase, resulting in disruption of the electron transport chain and impairing oxidative metabolism. Nervous and cardiac tissues, which have the highest oxygen demand (e.g., brain and heart), are especially sensitive to disruption of oxidative metabolism (Ammann 1986 Hall 1996). 

Nucleic acids are not the only biomolecules susceptible to damage by carotenoid degradation products. Degradation products of (3-carotene have been shown to induce damage to mitochondrial proteins and lipids (Siems et al., 2002), to inhibit mitochondrial respiration in isolated rat liver mitochondria, and to induce uncoupling of oxidative phosphorylation (Siems et al., 2005). Moreover, it has been demonstrated that the degradation products of (3-carotene, which include various aldehydes, are more potent inhibitors of Na-K ATPase than 4-hydroxynonenal, an aldehydic product of lipid peroxidaton (Siems et al., 2000). 

The administration of Qio or quercetin to rats protected against endotoxin-induced shock in rat brain [252]. It was found that the pretreatment with these antioxidants diminished the shock-induced increase in brain MDA and nitric oxide levels. Interesting data have been obtained by Yamamura et al. [253] who showed that ubiquinone Qi0 is able to play a double role in mitochondria. It was found that on the one hand, Q10 enhanced the release of hydrogen peroxide from antimycin A- or calcium-treated mitochondria, but on the other hand, it inhibited mitochondrial lipid peroxidation. It was proposed that Q10 acts as a prooxidant participating in redox signaling and as an antioxidant suppressing permeability transition and cytochrome c release. 

The answer is d. (Hardman, p 1019J Niclosamide is a halogenated salicylanilide derivative. It exerts its effect against cestodes by inhibition of mitochondrial oxidative phosphorylation in the parasites. The mechanism of action is also related to its inhibition of glucose and oxyrgen uptake in the parasite. 

Several mechanisms of fialuridine-induced hepatotoxicity have been suggested fialuridine and its metabolites inhibit mitochondrial DNA replication, leading to decreased mitochondrial DNA and mitochondrial ultrastructural defects [61]. Another mechanism suggested lies in pyruvate oxidation inhibition [62]. 

Oxidized LDL alter cellular functions role in cell death Oxidized LDL seem to be poorly degraded by lysosomal enzymes and accumulate in lysosomes altering in turn their functionality (Dean et al., 1997). It has been proposed that inhibition of oxidized LDL degradation and subsequent lipid accumulation may induce a destabilization of the acidic compartment, and lysosomal rupture with a relocation of lysosomal enzymes in the cytosol (li W et al, 1998). This process, also called endopepsis , occurs early and could precede mitochondrial dysfunction and cell death (Lossel et al., 1994). Moreover, oxidized LDL trigger a dysfunction of the intracellular proteolytic ubiquitin/proteasome pathway (early activation followed by inhibition)... 

Other work has indicated that chlordane and heptachlor are energy transfer inhibitors as evidenced by marked decreases in oxidative phosphorylation of rat hepatic mitochondria following in vitro incubation of the mitochondria with the pesticides (Ogata et al. 1989). Interestingly, even though heptachlor epoxide is more toxic than either chlordane or heptachlor in tests of general toxicity, it was less effective in inhibiting mitochondrial respiration. 

Amino-4-cyclopropylidenebutanoic acid (2S)-56, is a methylenecyclopro-pane substituted alanine which can be considered as a non-natural isomer of hypoglycine A 51. It has recently been synthesized racemic [61] and enantiome-rically pure [62]. Biological assays have shown that at relatively high concentration the 5,6-methanoamino acid 56 inhibits the metabolism of pyruvate into glucose, but 56 is not active in inducing the mitochondrial oxidation of fatty acids,Eq. (21) [63]. 

Impairment of mitochondrial jj-oxidation leads to accumulation of fat, resulting in steatosis. Examples are various tetracycline derivatives, valproic acid (used to treat seizures) and overdoses of aspirin [64—66]. Certain NSAIDs such as ibuprofen, ketoprofen and naproxen also have the ability to inhibit jj-oxidation [67-69]. 

Ponchaut, S., van Hoof, F. and Veitch, K. (1992) In vitro effects of valproate and valproate metabolites on mitochondrial oxidations. Relevance of CoA sequestration to the observed inhibitions. Biochemical Pharmacology, 43 (11), 2435-2442. 

---