Evaluation of the sensitization potential of volatile and semi-volatile organic compounds using the direct peptide reactivity assay

Kawakami, Tsuyoshi; Isama, Kazuo; Ikarashi, Yoshiaki; Jinno, Hideto

doi:10.2131/jts.45.725

Cited by 5 publications

(4 citation statements)

References 16 publications

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“…These adducts are collectively termed Advanced Lipooxidation End products (ALEs) and have been implicated in several pathologies . There is some evidence that protein modifications by RCS could be immunogenic (i.e., cause skin sensitization if applied topically - malondialdehyde, glyoxal, , and hexanal). However, the sheer variety of RCS that can be generated may mean that individual molecules are generated endogenously at levels below the sensitizing threshold.…”

Section: Understanding Protein Haptenationmentioning

confidence: 99%

Protein Haptenation and Its Role in Allergy

Aleksic,

Meng

2024

Chem. Res. Toxicol.

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Humans are exposed to numerous electrophilic chemicals either as medicines, in the workplace, in nature, or through use of many common cosmetic and household products. Covalent modification of human proteins by such chemicals, or protein haptenation, is a common occurrence in cells and may result in generation of antigenic species, leading to development of hypersensitivity reactions. Ranging in severity of symptoms from local cutaneous reactions and rhinitis to potentially life-threatening anaphylaxis and severe hypersensitivity reactions such as Stephen-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), all these reactions have the same Molecular Initiating Event (MIE), i.e. haptenation. However, not all individuals who are exposed to electrophilic chemicals develop symptoms of hypersensitivity. In the present review, we examine common chemistry behind the haptenation reactions leading to formation of neoantigens. We explore simple reactions involving single molecule additions to a nucleophilic side chain of proteins and complex reactions involving multiple electrophilic centers on a single molecule or involving more than one electrophilic molecule as well as the generation of reactive molecules from the interaction with cellular detoxification mechanisms. Besides generation of antigenic species and enabling activation of the immune system, we explore additional events which result directly from the presence of electrophilic chemicals in cells, including activation of key defense mechanisms and immediate consequences of those reactions, and explore their potential effects. We discuss the factors that work in concert with haptenation leading to the development of hypersensitivity reactions and those that may act to prevent it from developing. We also review the potential harnessing of the specificity of haptenation in the design of potent covalent therapeutic inhibitors.

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Section: Understanding Protein Haptenationmentioning

confidence: 99%

Protein Haptenation and Its Role in Allergy

Aleksic,

Meng

2024

Chem. Res. Toxicol.

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“…The Cys % depletion values determined by DPRA and CAS Registry Number (CAS RN) of a variety of chemicals were collected from published articles (Lalko et al, 2013;Yamashita et al, 2015;Dik et al, 2016;Kawakami et al, 2020;Hoffmann et al, 2022;Urbisch et al, 2015).…”

Section: Dataset Of Cys % Depletion Valuesmentioning

confidence: 99%

Development of an <i>in silico</i> consensus model for predicting the chemical reactivity to cysteine measured by the DPRA and its application to predict the skin sensitization potential of chemicals

Jojima,

Akahori

2023

Fundam. Toxicol. Sci.

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Covalent binding of chemicals to skin proteins represents the Molecular Initiating Event (MIE) of the skin sensitization process. We attempted to construct in silico models for predicting the reactivities of chemicals to cysteine measured by the Direct Peptide Reactivity Assay (DPRA) as a screening tool for skin sensitization potential of chemicals since there was no readily available in silico prediction model for reactivity classes of the DPRA. We used a dataset of 211 chemicals compiled based on the chemical reactivity to cysteine in the DPRA for model construction, and each chemical was classified as "Minimal-Low" or "Moderate-High" reactivity according to the percent cysteine depletion value in the DPRA. We constructed two independent classification models using two machine learning algorithms named Random Forest (RF) and Graph Convolutional Network (GCN), and a consensus model adopting prediction results when both of the GCN-based and the RF-based models were matched was also constructed. Performance evaluation showed that the RF-based model showed higher specificity than the GCN-based model and the GCN-based model showed higher sensitivity than the RF-based model. The consensus model showed high accuracy and high specificity of over 0.9. Comparison of the reactivity class predicted by the consensus model and the skin sensitization potential for humans revealed that all chemicals classified into the "Moderate-High" class were human skin sensitizers. In conclusion, the consensus model we constructed here may be a promising in silico screening tool to predict cysteine reactivity measured by the DPRA and skin sensitization potential of chemicals.

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“…For small molecules, this KE is addressed by the Direct Peptide Reactivity Assay (DPRA) assay, OECD TG442C, in which the depletion of model synthetic peptides containing either a cysteine or a lysine residue is quantified 196 . This test is usually positive for electrophilic agents, as shown for instance by the electrophile dimethyl fumarate (DMF), 197 which was found to be a strong contact sensitizer after the Chinese sofa/chair dermatitis epidemic 198 . Interestingly, an isosorbide‐DMF diester derivative was recently described as a potential nonsensitizer candidate for psoriasis, while maintaining Nrf2 activity 199 .…”

Section: Research Strategy For Nrf2 Modulators In Skin and Scalp Carementioning

confidence: 99%

“…electrophilic agents, as shown for instance by the electrophile dimethyl fumarate (DMF), 197 which was found to be a strong contact sensitizer after the Chinese sofa/chair dermatitis epidemic. 198 Interestingly, an isosorbide-DMF diester derivative was recently described as a potential nonsensitizer candidate for psoriasis, while maintaining Nrf2 activity.…”

Section: Human Safety Early Testingmentioning

confidence: 99%

NRF2 in dermo‐cosmetic: From scientific knowledge to skin care products

2022

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The skin is the organ that is most susceptible to the impact of the exposome.Located at the interface with the external environment, it protects internal organs through the barrier function of the epidermis. It must adapt to the consequences of the harmful effects of solar radiation, the various chemical constituents of atmospheric pollution, and wounds associated with mechanical damage: oxidation, cytotoxicity, inflammation, and so forth. In this biological context, a capacity to adapt to the various stresses caused by the exposome is essential; otherwise, more or less serious conditions may develop accelerated aging, pigmentation disorders, atopy, psoriasis, and skin cancers. Nrf2-controlled pathways play a key role at this level. Nrf2 is a transcription factor that controls genes involved in oxidative stress protection and detoxification of chemicals. Its involvement in UV protection, reduction of inflammation in processes associated with healing, epidermal differentiation for barrier function, and hair regrowth, has been demonstrated. The modulation of Nrf2 in the skin may therefore constitute a skin protection or care strategy for certain dermatological stresses and disorders initiated or aggravated by the exposome. Nrf2 inducers can act through different

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Evaluation of the sensitization potential of volatile and semi-volatile organic compounds using the direct peptide reactivity assay

Cited by 5 publications

References 16 publications

Protein Haptenation and Its Role in Allergy

Protein Haptenation and Its Role in Allergy

Development of an <i>in silico</i> consensus model for predicting the chemical reactivity to cysteine measured by the DPRA and its application to predict the skin sensitization potential of chemicals

NRF2 in dermo‐cosmetic: From scientific knowledge to skin care products

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