Diphenylthiourea, a common rubber chemical, is bioactivated to potent skin sensitizers
Journal article, 2011
Diphenylthiourea (DPTU) is a known skin sensitizer commonly used as a vulcanization accelerator in the production of synthetic rubber, for example, neoprene. The versatile usage of neoprene is due to the multifaceted properties of the material; for example, it is stretchable, waterproof, and chemical- and abrasion-resistant. The wide application of neoprene has resulted in numerous case reports of dermatitis patients allergic to DPTU. The mechanism by which DPTU works as a contact allergen has not been described; thus, the aim of the present study was to investigate if DPTU is a prohapten that can be activated by skin metabolism. The metabolic activation and covalent binding of (14)C-labeled DPTU to proteins were tested using a skinlike cytochrome P450 (P450) cocktail containing the five most abundant P450s found in human skin (CYP1A1, 1B1, 2B6, 2E1, and 3A5) and human liver microsomes. The incubations were carried out in the presence or absence of the metabolite trapping agents glutathione, methoxylamine, and benzylamine. The metabolism mixtures were analyzed by LC-radiochromatography, LC-MS, and LC-MS/MS. DPTU was mainly metabolically activated to reactive sulfoxides resulting in desulfurated adducts in both enzymatic systems used. Also, phenylisothiocyanate and phenylisocyanate were found to be metabolites of DPTU. The sensitizing capacity of the substrate (DPTU) and three metabolites was tested in the murine local lymph node assay. Two out of three metabolites tested were strong skin sensitizers, whereas DPTU itself, as previously known, was negative using this mouse model. In conclusion, DPTU forms highly reactive metabolites upon bioactivation by enzymes present in the skin. These metabolites are able to induce skin sensitization and are probable causes for DPTU allergy. To increase the possibilities of diagnosing contact allergy to DPTU-containing items, we suggest that suitable metabolites of DPTU should be used for screening testing.
Liver
Disease Models
Rubber
Animals
chemistry
Animal
Benzylamines
metabolism
Microsomes
chemistry
chemistry
chemistry
metabolism
Isothiocyanates
Humans
Hydroxylamines
Skin
Mice
Cytochrome P-450 Enzyme System
Allergic Contact
Dermatitis
Glutathione
analogs & derivatives
toxicity
metabolism
chemistry
enzymology
chemistry
Protein Binding
etiology
Thiourea
Author
Kristin Samuelsson
University of Gothenburg
Moa Andresen Bergström
AstraZeneca AB
Charlotte A Jonsson
University of Gothenburg
Gunnar Westman
Chalmers, Chemical and Biological Engineering, Organic Chemistry
Ann-Therese Karlberg
University of Gothenburg
Chemical Research in Toxicology
0893-228X (ISSN) 1520-5010 (eISSN)
Vol. 24 1 35-44Subject Categories
Chemical Engineering
Chemical Sciences
DOI
10.1021/tx100241z
PubMed
21073181