Chemical mechanisms for skin sensitization by aromatic compounds with hydroxy and amino groups.

It is well-known that aromatic diamino-, dihydroxy-, and amino-hydroxy compounds, with NH(2) and OH groups in ortho- or para-positions relative to each other, are strong skin sensitizers. In this paper, we analyze published potency and cross-reactivity data, whereby animals sensitized to one of these compounds are challenged with other compounds. The data are consistent with two parallel chemical reaction mechanisms: oxidation to electrophilic (protein reactive) quinones or quinone imines or formation of protein-reactive free radicals such as the Wurster salt, which can be formed by para-phenylene diamine. Compounds with NH(2) and OH groups meta to each other have also been found to be skin sensitizers, in some cases quite strong sensitizers. For these compounds, direct formation of quinones or quinone imines is not possible, and free radicals of the Wurster salt type are not favored. Here, we present a molecular mechanism to rationalize the sensitization potential of such compounds and, using the results of quantum mechanics calculations, show how this mechanism can explain observed structure-potency trends.

[1]  R. Bader,et al.  CHEMICAL EVIDENCE FOR A TRIPLET GROUND STATE FOR METHYLENE , 1960 .

[2]  Andreas Natsch,et al.  LC-MS-based characterization of the peptide reactivity of chemicals to improve the in vitro prediction of the skin sensitization potential. , 2008, Toxicological sciences : an official journal of the Society of Toxicology.

[3]  D. Liebler,et al.  Mitochondrial protein targets of thiol-reactive electrophiles. , 2008, Chemical research in toxicology.

[4]  D. Basketter,et al.  Investigation of the prohapten concept Cross reactions betwen 1,4‐substituted benzene derivatives in the guinea pig , 1988, Contact dermatitis.

[5]  S. Enoch,et al.  Identification of mechanisms of toxic action for skin sensitisation using a SMARTS pattern based approach , 2008, SAR and QSAR in environmental research.

[6]  H. Frey.  CHEMICAL EVIDENCE FOR THE GROUND STATE OF METHYLENE , 1960 .

[7]  S. Wakelin,et al.  Contact dermatitis from paraphenylenediamine used as a skin paint , 1998, Contact dermatitis.

[8]  Ian Kimber,et al.  Local Lymph Node Assays , 2004, Current protocols in toxicology.

[9]  Yu Shyr,et al.  Cytosolic and nuclear protein targets of thiol-reactive electrophiles. , 2006, Chemical research in toxicology.

[10]  E. Gleichmann,et al.  Cross‐sensitization to haptens: formation of common haptenic metabolites, T cell recognition of cryptic peptides, and true T cell cross‐reactivity , 2002, European journal of immunology.

[11]  David W Roberts,et al.  Determinants of skin sensitisation potential , 2008, Journal of applied toxicology : JAT.

[12]  K. Landsteiner,et al.  STUDIES ON THE SENSITIZATION OF ANIMALS WITH SIMPLE CHEMICAL COMPOUNDS , 1936, The Journal of experimental medicine.

[13]  D. Basketter,et al.  The skin sensitization potential of resorcinol: experience with the local lymph node assay , 2007, Contact dermatitis.

[14]  David W Roberts,et al.  Mechanistic applicability domains for nonanimal-based prediction of toxicological end points: general principles and application to reactive toxicity. , 2006, Chemical research in toxicology.

[15]  T. Sieber,et al.  Skin sensitization to p-phenylenediamine: the diverging roles of oxidation and N-acetylation for dendritic cell activation and the immune response. , 2009, The Journal of investigative dermatology.

[16]  Petra S Kern,et al.  TIMES-SS--a mechanistic evaluation of an external validation study using reaction chemistry principles. , 2007, Chemical research in toxicology.

[17]  P. Eyer,et al.  Reactions of the Wurster's blue radical cation with thiols, and some properties of the reaction products. , 1991, Chemico-biological interactions.

[18]  J. Lepoittevin.  Metabolism versus chemical transformation or pro‐ versus prehaptens? , 2006, Contact dermatitis.

[19]  S. Kundu,et al.  Thiyl (sulfhydryl/thiol) free radical reactions, vitamins, beta-carotene, and superoxide dismutase in oxidative stress: design and interpretation of enzymatic studies. , 1995, Methods in enzymology.

[20]  D W Roberts,et al.  Skin sensitization to eugenol and isoeugenol in mice: possible metabolic pathways involving ortho-quinone and quinone methide intermediates. , 1997, Chemical research in toxicology.

[21]  I Kimber,et al.  Classification of contact allergens according to potency: proposals. , 2003, Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association.

[22]  G Frank Gerberick,et al.  Allergic Contact Dermatitis , 1998, Springer Berlin Heidelberg.

[23]  H. Salem,et al.  Oxidants, antioxidants, and free radicals , 1997 .

[24]  Joachim Doll,et al.  Organization for Economic Cooperation and Development , 2021, International Organization.

[25]  J. Prins.  Directive 2003/98/EC of the European Parliament and of the Council , 2006 .

[26]  David W. Roberts,et al.  Optimisation of the Linear Alkyl Benzene Sulfonation Process for Surfactant Manufacture , 2003 .

[27]  Kristina Luthman,et al.  Allergic contact dermatitis--formation, structural requirements, and reactivity of skin sensitizers. , 2008, Chemical research in toxicology.

[28]  K. Landsteiner,et al.  STUDIES ON THE SENSITIZATION OF ANIMALS WITH SIMPLE CHEMICAL COMPOUNDS , 1935, The Journal of experimental medicine.

[29]  R J Fielder,et al.  Local lymph node assay - validation, conduct and use in practice. , 2002, Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association.

[30]  Grace Patlewicz,et al.  Electrophilic chemistry related to skin sensitization. Reaction mechanistic applicability domain classification for a published data set of 106 chemicals tested in the mouse local lymph node assay. , 2007, Chemical research in toxicology.

[31]  J. Friend,et al.  A Polarographic study of some Wurster salts , 1958 .

[32]  Maja Aleksic,et al.  Reactivity profiling: covalent modification of single nucleophile peptides for skin sensitization risk assessment. , 2009, Toxicological sciences : an official journal of the Society of Toxicology.

[33]  E. Gould.  Mechanism and Structure in Organic Chemistry , 1969 .

[34]  Carsten Goebel,et al.  Proposal for a risk assessment methodology for skin sensitization based on sensitization potency data. , 2003, Regulatory toxicology and pharmacology : RTP.

[35]  Ian Kimber,et al.  The local lymph node assay: past, present and future , 2002, Contact dermatitis.

[36]  G Frank Gerberick,et al.  Quantification of chemical peptide reactivity for screening contact allergens: a classification tree model approach. , 2007, Toxicological sciences : an official journal of the Society of Toxicology.

[37]  Joan Eilstein,et al.  Synthesis and reactivity toward nucleophilic amino acids of 2,5-[13C]-dimethyl-p-benzoquinonediimine. , 2006, Chemical research in toxicology.

[38]  I Kimber,et al.  The local lymph node assay: a viable alternative to currently accepted skin sensitization tests. , 1996, Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association.