Diphenylthiourea, a common rubber chemical, is bioactivated to potent skin sensitizers
Artikel i vetenskaplig tidskrift, 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.

Glutathione

Skin

Disease Models

metabolism

chemistry

Protein Binding

chemistry

chemistry

Benzylamines

Animal

Hydroxylamines

enzymology

metabolism

Dermatitis

toxicity

metabolism

Thiourea

etiology

Liver

Microsomes

chemistry

Cytochrome P-450 Enzyme System

Isothiocyanates

Allergic Contact

analogs & derivatives

Animals

Rubber

Mice

Humans

chemistry

chemistry

Författare

Kristin Samuelsson

Göteborgs universitet

Moa Andresen Bergström

AstraZeneca Sweden

Charlotte A Jonsson

Göteborgs universitet

Gunnar Westman

Chalmers, Kemi- och bioteknik, Organisk kemi

Ann-Therese Karlberg

Göteborgs universitet

Chemical Research in Toxicology

0893-228X (ISSN) 1520-5010 (eISSN)

Vol. 24 35-44

Ämneskategorier

Kemiteknik

Kemi

DOI

10.1021/tx100241z

PubMed

21073181