Uncoupling action of 2,4-dinitrophenols, 2-trifluoromethylbenzimidazoles and certain other pesticide chemicals upon mitochondria from different sources and its relation to toxicity

Ilivicky, Jovita; Casida, John E.

doi:10.1016/0006-2952(69)90252-4

Cited by 73 publications

(25 citation statements)

References 21 publications

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“…The intramitochondrial vs. extramitochondrial calcium ion balance, the chemical inhibition of electron transport, and the excessive generation of ROS are critically important and interrelated factors that can lead to the destruction of the organelle and release of apoptotic factors that can cascade under some circumstances to destroy the entire cell. Mitochondria from different sources vary in terms of susceptibility to mitochondrial toxicants [75] and vary substantially in morphology and distribution among different cell types [11]. Beyond histological examination of tissue sections by electron or confocal microscopy post-mortem, mitochondrial toxicity is studied by in vitro means using cultured cell lines, isolated mitochondria, submitochondrial particles, or peripheral cells.…”

Section: Methods For Assessing Mitochondrial Functionmentioning

confidence: 99%

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Drug-Associated Mitochondrial Toxicity and its Detection

Amacher¹

2005

CMC

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Mitochondrial dysfunction is a fundamental mechanism in the pathogenesis of several significant toxicities in mammals, especially those associated with the liver, skeletal and cardiac muscle, and the central nervous system. These changes can also occur as part of the natural aging process and have been linked to cellular mechanisms in several human disease states including Parkinson's and Alzheimer's, as well as ischemic perfusion injury and the effects of hyperglycemia in diabetes mellitus. Our knowledge of the effects of xenobiotics on mitochondrial function has expanded to the point that chemical structure and properties can guide the pharmaceutical scientist in anticipating mitochondrial toxicity. Recognition that maintenance of the mitochondrial membrane potential is essential for normal mitochondrial function has resulted in the development of predictive cell-based or isolated mitochondrial assay systems for detecting these effects with new chemical entities. The homeostatic role of some uncoupling proteins, differences in mitochondrial sensitivity to toxicity, and the pivotal role of mitochondrial permeability transition (MPT) as the determinant of apoptotic cell death are factors that underlie the adverse effects of some drugs in mammalian systems. In order to preserve mitochondrial integrity in potential target organs during therapeutic regimens, a basic understanding of mitochondrial function and its monitoring in the drug development program are essential. Toward this end, this review focuses on two topics, (1) the specific effects of xenobiotics on mitochondrial structure and function and (2) a summarization of current methods for quantifying these changes in a preclinical toxicology laboratory.

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Section: Methods For Assessing Mitochondrial Functionmentioning

confidence: 99%

“…Sensitivity differences to uncouplers among species and tissues have been reported [75] with mouse brain mitochondria more sensitive to uncoupling than mouse liver mitochondria. Rat brain and liver mitochondria differ in the baseline behavior of the MPT and responses to modifiers of PT [76].…”

Section: Mitochondrial Targets Leading To Drug Toxicitymentioning

confidence: 96%

Drug-Associated Mitochondrial Toxicity and its Detection

Amacher¹

2005

CMC

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“…It has also been shown that DNP inhibits chloride channel of erythrocytes [11] and blocks glutathione-S-conjugate forming ATP-ase [12]. Comparison of toxic doses for mice with uncoupling concentrations for isolated mitochondria has revealed poor correlation of these parameters for a large set of DNP analogues as well as for some other uncouplers [13]. These findings suggest that the toxic effect of at least some uncouplers in vivo could be unrelated to their action on mitochondria.…”

Section: Introductionmentioning

confidence: 99%

Penetrating Cations Enhance Uncoupling Activity of Anionic Protonophores in Mitochondria

et al. 2013

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Protonophorous uncouplers causing a partial decrease in mitochondrial membrane potential are promising candidates for therapeutic applications. Here we showed that hydrophobic penetrating cations specifically targeted to mitochondria in a membrane potential-driven fashion increased proton-translocating activity of the anionic uncouplers 2,4-dinitrophenol (DNP) and carbonylcyanide-p-trifluorophenylhydrazone (FCCP). In planar bilayer lipid membranes (BLM) separating two compartments with different pH values, DNP-mediated diffusion potential of H+ ions was enhanced in the presence of dodecyltriphenylphosphonium cation (C12TPP). The mitochondria-targeted penetrating cations strongly increased DNP- and carbonylcyanide m-chlorophenylhydrazone (CCCP)-mediated steady-state current through BLM when a transmembrane electrical potential difference was applied. Carboxyfluorescein efflux from liposomes initiated by the plastoquinone-containing penetrating cation SkQ1 was inhibited by both DNP and FCCP. Formation of complexes between the cation and CCCP was observed spectophotometrically. In contrast to the less hydrophobic tetraphenylphosphonium cation (TPP), SkQ1 and C12TPP promoted the uncoupling action of DNP and FCCP on isolated mitochondria. C12TPP and FCCP exhibited a synergistic effect decreasing the membrane potential of mitochondria in yeast cells. The stimulating action of penetrating cations on the protonophore-mediated uncoupling is assumed to be useful for medical applications of low (non-toxic) concentrations of protonophores.

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“…It causes toxicity by uncoupling oxidative phosphorylation in the mitochondria of cells (Ilvicky & Casida, 1969 ;Simon, 1953). It causes ' dinitrophenol poisoning ' to man exposed to contaminated environments (Leftwich et al, 1982).…”

Section: Introductionmentioning

confidence: 99%

Rhodococcus koreensis sp. nov., a 2,4-dinitrophenol-degrading bacterium.

Yoon¹,

Cho²,

Kang³

et al. 2000

International Journal of Systematic and Evolutionary Microbiology

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A 2,4-dinitrophenol-degrading bacterial strain, DNP505 T , which was isolated from an industrial wastewater, was taxonomically studied by a polyphasic approach using phenotypic, chemotaxonomic and genetic methods. Strain DNP505T has a cell wall of chemotype IV containing meso-diaminopimelic acid, arabinose and galactose. The predominant menaquinone is MK-8(H 2 ). Mycolic acids contain 43-53 carbon atoms. Strain DNP505T has a cellular fatty acid profile containing straight-chain saturated, unsaturated and 10-methylbranched fatty acids and has C 16 :0 as the major fatty acid. The DNA GMC content is 66 mol %. Strain DNP505T formed a coherent cluster with Rhodococcus species in a phylogenetic inference based on 16S rDNA sequences. Interestingly, strain DNP505T was found to have two types of 16S rDNA sequence, which showed 10 bp sequence differences (993 % nucleotide similarity). Its differences in some phenotypic characteristics and its genetic distinctiveness indicate that strain DNP505T is separate from Rhodococcus species described previously. It is therefore proposed that strain DNP505 Keywords : Rhodococcus koreensis sp. nov., 2,4-dinitrophenol degradation, polyphasic taxonomy INTRODUCTIONNitroaromatic compounds are frequently used as building blocks for dyes, plastics, explosives, herbicides and pesticides, and are also important as solvents (Lenke et al., 1992 ;Marvin-Sikkema & de Bont, 1994). However, despite their industrial importance, nitroaromatic compounds are in most cases highly toxic to living organisms, including microorganisms. They are abundantly present in nature and, in particular, are found as contaminants in waste waters, rivers and herbicide-or pesticide-treated soils (Lenke et al., 1992 ;Marvin-Sikkema & de Bont, 1994). In spite of the toxicity of nitroaromatic compounds, several micro-organisms that are able to convert or degrade nitroaromatic compounds have been found to exist in nature (Marvin-Sikkema & de Bont, 1994 aromatic-contaminated sites (Bruhn et al., 1987 ;Cho et al., 1998 ;Zeyer & Kearney, 1984).2,4-Dinitrophenol is a well known toxic aromatic compound. It causes toxicity by uncoupling oxidative phosphorylation in the mitochondria of cells (Ilvicky & Casida, 1969 ;Simon, 1953). It causes ' dinitrophenol poisoning ' to man exposed to contaminated environments (Leftwich et al., 1982). The classic syndrome of ' dinitrophenol poisoning ' includes lassitude, malaise, headache, increased perspiration, thirst, profound weight loss and respiratory failure (Leftwich et al., 1982). Some bacterial strains have been reported to degrade 2,4-dinitrophenol (Hess et al., 1990 ;Lenke et al., 1992). Such useful strains utilizing 2,4-dinitrophenol as sole carbon and nitrogen sources have been isolated in our laboratory. Among them, one strain (DNP505) was found to have high ability to utilize or degrade 2,4-dinitrophenol and was considered to be a member of the genus Rhodococcus. The aim of this study was to determine the exact phylogenetic position of strain DNP505. We describe its morphological ...

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Uncoupling action of 2,4-dinitrophenols, 2-trifluoromethylbenzimidazoles and certain other pesticide chemicals upon mitochondria from different sources and its relation to toxicity

Cited by 73 publications

References 21 publications

Drug-Associated Mitochondrial Toxicity and its Detection

Drug-Associated Mitochondrial Toxicity and its Detection

Penetrating Cations Enhance Uncoupling Activity of Anionic Protonophores in Mitochondria

Rhodococcus koreensis sp. nov., a 2,4-dinitrophenol-degrading bacterium.

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