Cross-species comparison of chemical inhibition of human and Xenopus iodotyrosine deiodinase.

Abstract

The transition to include in vitro-based data in chemical hazard assessment has resulted in the development and implementation of screening assays to cover a diversity of biological pathways, including recently added assays to interrogate chemical disruption of proteins relevant to thyroid signaling pathways. Iodotyrosine deiodinase (IYD), the iodide recycling enzyme, is one such thyroid-relevant endpoint for which a human-based screening assay has recently been developed and used to screen large libraries of chemicals. Presented here is the development of an amphibian IYD inhibition assay and its implementation to conduct a cross-species comparison between chemical inhibition of mammalian and non-mammalian IYD enzyme activity. The successful development of an amphibian IYD inhibition assay was based on demonstration of sufficient IYD enzyme activity in several tissues collected from larval Xenopus laevis. With this new assay, 154 chemicals were tested in concentration-response to provide a basis for comparison of relative chemical potency to results obtained from the human IYD assay. Most chemicals exhibited similar inhibition in both assays, with less than 25% variation in median inhibition for 120 of 154 chemicals and 85% concordance in categorization of "active" (potential IYD inhibitor) versus "inactive". For chemicals that produced 50% or greater inhibition in both assays, rank-order potency was similar, with the majority of the IC50s varying by less than 2-fold (and all within an order of magnitude). Most differences resulted from greater maximum inhibition or higher chemical potency observed with human IYD. This strong cross-species agreement suggests that results from the human-based assay would be conservatively predictive of chemical effects on amphibian IYD.