Mechanism of thermal decomposition of thiourea derivatives

Lizarraga, Elena; Zabaleta, C.; Palop, Juan Antonio

doi:10.1007/s10973-007-8489-6

Cited by 9 publications

(7 citation statements)

References 12 publications

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“…m/z 136 corresponds to PITC and m/z 119 to C 6 H 5 -NCNH 2 ; the latter was also present as a product ion of A4 and A7. The observed fragment ion at m/z 94 is suggested to be anilinium ion, and the ion at m/z 91 is (C 7 H 7 ) + as previously reported (38).…”

supporting

confidence: 80%

“…From A7, protonated BA is formed and detected as m / z 108. Collision-induced dissociation of BA products identified in this study did all produce the mass of 91, which likely is the tropylium ion C 7 H 7 + . Proposed structures of adducts A2, A3, and A5 found in the incubates of MA and NADPH are shown in Scheme .…”

Section: Resultsmentioning

confidence: 67%

“…A6 and A8 are formed from the reactive metabolites PIC and PITC (Scheme ), respectively. PITC may also be formed as a thermal decomposition product of DPTU , and small amounts of A8 were also found in the controls (data not shown). Isothiocyanates may be metabolically converted into the corresponding, and even more reactive, isocyanate PIC , , and thus, the adduct A6 was formed as a result of further metabolism of PITC to PIC.…”

Section: Resultsmentioning

confidence: 85%

“…Several thiourea-containing compounds have previously been shown to form reactive sulfoxide intermediates with alkylating potential of the metabolites (37,47). The radioactivity observed in the pellet from the NADPH-free control experiments is thought to correspond to binding of PITC, formed from degradation of DPTU (38). Although previous studies (37,47) support the opinion that thioureas need to be oxidized into unstable intermediary metabolites to achieve an alkylating potential, it cannot be excluded that DPTU also is inherently reactive toward nucleophiles.…”

Section: Discussionmentioning

confidence: 98%

“…Experimental studies in mice showed cross-reactivity between PITC and PIC, corroborating the in vitro results. Because of the thermal instability of DPTU (38), PITC could also be formed as a degradation product and thus be present in, for example, neoprene and PVC products, as these are produced at high temperatures. Thus, it is likely that people using DPTU-containing items are simultaneously exposed to DPTU and PITC.…”

Section: Discussionmentioning

confidence: 99%

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Diphenylthiourea, a Common Rubber Chemical, Is Bioactivated to Potent Skin Sensitizers

Samuelsson

Bergström

Jonsson

et al. 2010

Chem. Res. Toxicol.

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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.

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supporting

confidence: 80%

Section: Resultsmentioning

confidence: 67%