Differentiation of the mechanism of micronuclei induced by cysteine and glutathione conjugates of methylenedi-p-phenyl diisocyanate from that of 4,4′-methylenedianiline

Zhong, Beilong; Depree, Gary J.; Siegel, Paul D.

doi:10.1016/s1383-5718(01)00246-7

Cited by 7 publications

(5 citation statements)

References 22 publications

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“…MDI-GSH-induced MN had a significant increase in the number of anti-kineticore antibody labeled MN. These results suggest that MDI-GSH MN induction was mediated through disruption of microtubules (32). The ultimate asthmogenic hapten-protein complex may preferentially form through the thiocarbamate intermediate, rather than directly by reaction with the dNCO.…”

Section: Rdi -mentioning

confidence: 84%

“…Alternatively, bis-thiocarbamates may have some protective effect since at least part of the hydrolysis proceeds through the BAc2 mechanism resulting in nonprotein reactive intermediates and products. In our previous studies (32) of Chinese hamster fibroblasts (V79) exposed to an MDI-GSH (relatively insoluble) adduct, we noted a dose-dependent increased micronuclei (MN) formation and number of cells in metaphase. Intracellular precipitants were also noted.…”

Section: Rdi -mentioning

confidence: 88%

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Kinetics and Mechanistic Studies of the Hydrolysis of Diisocyanate-Derived Bis-thiocarbamates of Cysteine Methyl Ester

Chipinda

Stetson

Depree

et al. 2006

Chem. Res. Toxicol.

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Diisocyanates (dNCOs) are the most commonly reported cause of chemically induced occupational asthma, but the ultimate antigenic form is unknown. Reactions of the three most common monomeric dNCOs, hexamethylene dNCO (HDI), methylene diphenylisocyanate (MDI), and toluene dNCO (TDI), with cysteine methyl ester (CME) gave the corresponding bis-dithiocarbamates (HDI-CME, TDI-CME, and MDI-CME). The dissociation kinetics of these bis-thiocarbamates, in aqueous conditions, was followed spectrophotometrically under varying pH and temperature conditions. Reaction of the adducts with methylamine or human serum albumin (HSA) produced diurea, monourea, and diamine products, and this was consistent with the base-catalyzed elimination reaction (E1cB) pathway being the dominant, but not exclusive, dissociation mechanism. The hydrolysis of the adducts was first-order with respect to OH(-) concentration and overall second-order (HDI-CME, k = 3.36 x 10(2) M(-)(1) min(-)(1); TDI-CME, k = 2.49 x 10(4) M(-)(1) min(-)(1); and MDI-CME, k = 5.78 x 10(4) M(-)(1) min(-)(1) at pH 7.4) with deviation from second-order when the dNCO had an aromatic functional group. Arrhenius plots gave activation energies (HDI-CME, E(a) = 70.6 kJ/mol; TDI-CME, E(a) = 46.1 kJ/mol; and MDI-CME, E(a) = 44.5 kJ/mol) that were consistent with the following order of stability: HDI-CME > TDI-CME > MDI-CME. Therefore, the stability of different dNCO-derived thiocarbamates in aqueous environments can vary greatly. Thiocarbamate dissociation rates and type of products formed may potentially influence antigenicity and subsequent hypersensitivity/toxic reactions following dNCO exposures.

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Section: Rdi -mentioning

confidence: 84%

Section: Rdi -mentioning

confidence: 88%

Kinetics and Mechanistic Studies of the Hydrolysis of Diisocyanate-Derived Bis-thiocarbamates of Cysteine Methyl Ester

Chipinda

Stetson

Depree

et al. 2006

Chem. Res. Toxicol.

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“…Reaction in hydrogen carbonate solution according to a protocol given by Day et al for TDI (6) resulted in the degradation of the desired thiocarbamate, although it was initially formed under these conditions. Very recently the synthesis of the bis adduct of MDI 3 in an acetonitrile/ water mixture has been published (18). The characterization of the compound was done by solid-state carbon NMR.…”

Section: Resultsmentioning

confidence: 99%

Synthesis, Characterization, and Solvolysis of Mono- and Bis-S-(glutathionyl) Adducts of Methylene-bis-(phenylisocyanate) (MDI)

Reisser

Schmidt

Brown

2002

Chem. Res. Toxicol.

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Bifunctional isocyanates are highly reactive compounds that undergo nucleophilic attack by a variety of functional groups available in the biological system. While the etiology of the respiratory disease caused by diisocyanates is not fully understood, a great deal of research has been performed to elucidate the chemical mechanisms involved in the direct and indirect effects of these compounds. Since adducts of isocyanates are found not only to proteins along the entire respiratory tree but also to proteins in the circulatory system, it is likely that a transport mechanism for the isocyanate from the respiratory to the circulatory system exists. The initial reaction of isocyanates with cellular thiols to form thiocarbamates, which are known to release the isocyanate under physiological conditions, is believed to provide a possible carrier mechanism for the isocyanate functional group. Previous work with aliphatic mono-isocyanates and the aromatic diisocyanate toluene diisocyanate has demonstrated the feasibility of this mechanism. Adding to this database, the products of the reaction of the highly water-insoluble, low vapor pressure, methylene-bis-(phenylisocyanate) (MDI) with glutathione were synthesized, and their chemical stability under various pH and buffer conditions was tested. Novel synthetic routes were developed for both the mono- and bis-S-(glutathionyl) adducts with MDI that yielded each compound in analytically pure form. Both compounds were found to be unstable under mild basic conditions (phosphate-buffered saline, pH 7.4, and NaHCO(3), pH 8.2), however to a different degree. Furthermore, a significant influence of the pH value (the rate of degradation increases with pH) and the concentration of free glutathione (increasing thiol stabilizes the adduct) on the stability was observed, indicating a base-catalyzed mechanism of the degradation/formation of the thiocarbamate bond. Unlike the monoadduct, which forms almost exclusively the polyurea upon degradation, a variety of products were formed upon degradation of the bis adduct. Though the disappearance of the bis adduct was complete as measured by HPLC, (1)H NMR spectra showed the existence of residual thiocarbamate bonds in the final mixture. In both cases, no evidence of the free methylene-bis-phenylamine (MDA) could be detected under the applicable conditions.

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“…The MDI-GSH conjugate produced an increase in cells in the metaphase and intracellular precipitates (Zhong and Siegel 2000). In a further study, the increase in micronuclei produced by the conjugates was confirmed and a disturbance of the mitotic spindle was demonstrated by staining the kinetochores (Zhong et al 2001). As DMSO was used as the solvent in both studies, solvolytic effects cannot be excluded, however.…”

Section: In Vitromentioning

confidence: 87%

4,4′‐Methylene diphenyl diisocyanate (MDI) [101‐68‐8] and “polymeric” MDI (PMDI) [9016‐87‐9] [MAK Value Documentation, 2008]

2015

The MAK‐Collection for Occupational Health and Safety

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The article contains sections titled: Toxic Effects and Mode of Action Mechanism of Action Toxicokinetics and Metabolism Absorption, distribution, elimination Metabolism Binding to macromolecules/biological monitoring Effects in Humans Single exposures Repeated exposure Local effects on skin and mucous membranes Allergenic effects Reproductive and developmental toxicity Genotoxicity Carcinogenicity Animal Experiments and in vitro Studies Acute toxicity Subacute, subchronic and chronic toxicity Local effects on skin and mucous membranes Allergenic effects Reproductive toxicity Genotoxicity Carcinogenicity Manifesto (MAK value, classification)

show abstract

Differentiation of the mechanism of micronuclei induced by cysteine and glutathione conjugates of methylenedi-p-phenyl diisocyanate from that of 4,4′-methylenedianiline

Cited by 7 publications

References 22 publications

Kinetics and Mechanistic Studies of the Hydrolysis of Diisocyanate-Derived Bis-thiocarbamates of Cysteine Methyl Ester

Kinetics and Mechanistic Studies of the Hydrolysis of Diisocyanate-Derived Bis-thiocarbamates of Cysteine Methyl Ester

Synthesis, Characterization, and Solvolysis of Mono- and Bis-S-(glutathionyl) Adducts of Methylene-bis-(phenylisocyanate) (MDI)

4,4′‐Methylene diphenyl diisocyanate (MDI) [101‐68‐8] and “polymeric” MDI (PMDI) [9016‐87‐9] [MAK Value Documentation, 2008]

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