Jump to main content
Jump to site search


Application of the direct peptide reactivity assay (DPRA) to inorganic compounds: a case study of platinum species

Author affiliations

Abstract

The in chemico Direct Peptide Reactivity Assay (DPRA) was developed as a non-animal, relatively high throughput, screening tool for skin sensitization potential. Although the Adverse Outcome Pathway (AOP) for respiratory sensitization remains to be fully elucidated, it is recognized that the molecular initiation event for both skin and respiratory sensitization to low molecular weight chemicals involves haptenation with proteins. The DPRA examines the reactivity of a test compound to two model peptides (containing either cysteine or lysine) and consequently is able to screen for both skin and respiratory sensitization potential. The DPRA was primarily developed for and validated with organic compounds and assessment of the applicability of the assay to metal compounds has received only limited attention. This paper reports the successful application of the DPRA to a series of platinum compounds, including hexachloroplatinate and tetrachloroplatinate salts, which are some of the most potent chemical respiratory sensitizers known. Eleven platinum compounds were evaluated using the DPRA protocol as detailed by Lalko et al., with only minor modification. Two palladium compounds with structures similar to that of the platinum species studied and cobalt chloride were additionally tested for comparison. The hexachloroplatinate and tetrachloroplatinate salts showed exceptionally high reactivity with the cysteine peptide (EC15 values of 1.4 and 14 μM, respectively). However, for platinum compounds (e.g. hydrogen hexahydroxyplatinate and tetraammineplatinum) where clinical and epidemiological evidence indicates limited sensitization potential, the cysteine DPRA showed only minor or no reactivity (EC15 values of 24 600 and >30 000 μM, respectively). The outcomes of the lysine peptide assays were less robust and where EC15 was measurable, values were substantially higher than the corresponding results from the cysteine assay. This work supports the value of in chemico peptide reactivity as a metric for assessment of platinum sensitization potential and therefore in screening of new platinum compounds for low or absent sensitization potential. Additional studies are required to determine whether the DPRA may be successfully applied to other metals. We provide details on method modifications and precautions important to the success of the DPRA in the assessment of metal reactivity.

Graphical abstract: Application of the direct peptide reactivity assay (DPRA) to inorganic compounds: a case study of platinum species

Back to tab navigation

Supplementary files

Publication details

The article was received on 04 Sep 2019, accepted on 04 Nov 2019 and first published on 20 Nov 2019


Article type: Paper
DOI: 10.1039/C9TX00242A
Toxicol. Res., 2019, Advance Article

  •   Request permissions

    Application of the direct peptide reactivity assay (DPRA) to inorganic compounds: a case study of platinum species

    J. D. C. Hemming, M. Hosford and M. M. Shafer, Toxicol. Res., 2019, Advance Article , DOI: 10.1039/C9TX00242A

Search articles by author

Spotlight

Advertisements