QSAR modeling of oxidative stress in vitro following hepatocyte exposures to halogenated methanes

Geiss, Kevin T.; Frazier, John M.

doi:10.1016/s0887-2333(01)00063-7

Cited by 16 publications

(21 citation statements)

References 22 publications

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“…Oxidative stress induction by THMs has been demonstrated previously by use of an assay with rat hepatocytes together with a good correlation between E LUMO and oxidative stress induction with comparable r 2 -values (Geiss and Frazier 2001). ECs from the genotoxicity assays also correlated significantly with E LUMO (r 2 = 0.96 for p53-bla, Fig.…”

Section: <>supporting

confidence: 71%

“…DNA-reactive and protein/peptide reactive chemicals can be further characterized by their electrophilic properties with E LUMO as a measure of electrophilicity (Schultz et al 2006). E Lumo is a common electrophilicity descriptor frequently used for QSAR analyses of reactive compounds (Burrow and Modelli 2013, Geiss and Frazier 2001, Huang et al 2007, Schultz et al 2006. Calculated E LUMO values differ significantly depending on the applied model while the relative E LUMO energies within a series of congeners are commonly quite comparable (Burrow and Modelli 2013).…”

Section: Relationship Between Reactivity Descriptors and Effectsmentioning

confidence: 99%

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Fingerprinting the reactive toxicity pathways of 50 drinking water disinfection by-products

et al. 2016

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A set of nine in vitro cellular bioassays indicative of different stages of the cellular toxicity pathway was applied to 50 disinfection by-products (DBPs) to obtain a better understanding of the commonalities and differences in the molecular mechanisms of reactive toxicity of DBPs. An Eschericia coli test battery revealed reactivity towards proteins/peptides for 64% of the compounds. 98% activated the NRf2-mediated oxidative stress response and 68% induced an adaptive stress response to genotoxic effects as indicated by the activation of the tumor suppressor protein p53. All DBPs reactive towards DNA in the E. coli assay and activating p53 also induced oxidative stress, confirming earlier studies that the latter could trigger DBP's carcinogenicity. The energy of the lowest unoccupied molecular orbital ELUMO as reactivity descriptor was linearly correlated with oxidative stress induction for trihalomethanes (r(2)=0.98) and haloacetamides (r(2)=0.58), indicating that potency of these DBPs is connected to electrophilicity. However, the descriptive power was poor for haloacetic acids (HAAs) and haloacetonitriles (r(2) (<) 0.06). For HAAs, we additionally accounted for speciation by including the acidity constant with ELUMO in a two-parameter multiple linear regression model. This increased r(2) to >0.80, indicating that HAAs' potency is connected to both, electrophilicity and speciation. Based on the activation of oxidative stress response and the soft electrophilic character of most tested DBPs we hypothesize that indirect genotoxicity-e.g., through oxidative stress induction and/or enzyme inhibition-is more plausible than direct DNA damage for most investigated DBPs. The results provide not only a mechanistic understanding of the cellular effects of DBPs but the effect concentrations may also serve to evaluate mixture effects of DBPs in water samples.

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Section: <>supporting

confidence: 71%

Section: Relationship Between Reactivity Descriptors and Effectsmentioning

confidence: 99%

Fingerprinting the reactive toxicity pathways of 50 drinking water disinfection by-products

et al. 2016

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“…The electrophilic (ω) and nucleophilic (ω − ) indices have been demonstrated to be reliable descriptors for a variety of electrophile-nucleophile interactions 8,18,27–28 .…”

Section: Hsab Definitions: Soft and Hard Electrophiles And Nucleophilesmentioning

confidence: 99%

Application of the Hard and Soft, Acids and Bases (HSAB) Theory to Toxicant–Target Interactions

LoPachin

Gavin

DeCaprio

et al. 2011

Chem. Res. Toxicol.

271

251

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Many chemical toxicants and/or their active metabolites are electrophiles that cause cell injury by forming covalent bonds with nucleophilic targets on biological macromolecules. Covalent reactions between nucleophilic and electrophilic reagents are however discriminatory, since there is a significant degree of selectivity associated with these interactions. Over the course of the past few decades, the theory of Hard and Soft, Acid and Bases (HSAB) has proven to be a useful tool in predicting the outcome of such reactions. This concept utilizes the inherent electronic characteristic of polarizability to define, for example, reacting electrophiles and nucleophiles as either hard or soft. These HSAB definitions have been successfully applied to chemical-induced toxicity in biological systems. Thus, according to this principle, a toxic electrophile reacts preferentially with biological targets of similar hardness or softness. The soft/hard classification of a xenobiotic electrophile has obvious utility in discerning plausible biological targets and molecular mechanisms of toxicity. The purpose of this Perspective is to discuss the HSAB theory of electrophiles and nucleophiles within a toxicological framework. In principle, covalent bond formation can be described by using the properties of their outermost or frontier orbitals. Because these orbital energies for most chemicals can be calculated using quantum mechanical models, it is possible to quantify the relative softness (σ) or hardness (η) of electrophiles or nucleophiles and to subsequently convert this information into useful indices of reactivity. This atomic level information can provide insight into the design of corroborative laboratory research and thereby help investigators discern corresponding molecular sites and mechanisms of toxicant action. The use of HSAB parameters has also been instrumental in the development and identification of potential nucleophilic cytoprotectants that can scavenge toxic electrophiles. Clearly, the difficult task of delineating molecular sites and mechanisms of toxicant action can be facilitated by the application of this quantitative approach.

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“…Often, very good correlations (>0.95) can be identified between these endpoints and certain chemical descriptors, e.g. molecular orbital energy (Geiss and Frazier, 2001). However, single QSARs do not solve many problems and the highly specific nature basically prevents them from being applied to other endpoints of interest.…”

Section: Structure-activity Relationships (Sars)mentioning

confidence: 99%

Development of an Integrated Toxicity Assessment System for use in Operational Deployment and Materials Development

Geiss¹

2006

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This report is published in the interest of scientific and technical information exchange, and its publication does not constitute the Government's approval or disapproval of its ideas or findings.Public reporting burden for this collection of information is estimated to average 1 hour per response, induding the time for reviewing instructions, searching data sources, gathering and maintaining the data needed, and completing and reviewing the collection of information. Send comments regarding this burden estimate or any other aspect of this collection of information, including suggestions for redudng this burden to

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QSAR modeling of oxidative stress in vitro following hepatocyte exposures to halogenated methanes

Cited by 16 publications

References 22 publications

Fingerprinting the reactive toxicity pathways of 50 drinking water disinfection by-products

Fingerprinting the reactive toxicity pathways of 50 drinking water disinfection by-products

Application of the Hard and Soft, Acids and Bases (HSAB) Theory to Toxicant–Target Interactions

Development of an Integrated Toxicity Assessment System for use in Operational Deployment and Materials Development

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