Dr. Curt Omiecinski’ s lab receives the Board of Publications Award for the Best Paper in Toxicological Sciences
Posted: March 13, 2012
Phthalates and other endocrine-disruptive chemicals are manufactured in large quantities for use as plasticizers and other commercial applications, resulting in ubiquitous human exposure and thus, concern regarding their toxicity. Innate defense against small molecule exposures is controlled in large part by the constitutive androstane receptor (CAR) and the pregnane X receptor (PXR). The human CAR gene undergoes multiple alternative splicing events resulting in variant receptors, and one of these variant receptors (CAR2) is potently and specifically activated by phthalate. The authors hypothesized that alternative splicing is a mechanism for increasing CAR’s functional diversity, broadening the human receptors’ repertoire of response to environmental xenobiotics.
In this paper, the authors used transactivation and mammalian two-hybrid assays to demonstrate differential selectivity of endocrine-disrupting chemicals on CAR and PXR variants. These results offer an important insight into the mechanism whereby alternate splicing of receptors results in an enhanced capability of receptors to distinguish among a broad range of xenobiotics that possess similar chemical properties. In this way, variant receptors possess distinct ligand-selective activation profiles.
This paper greatly extends our understanding of a fundamental mystery of toxicology—How are a relatively small number of xenosensing receptors able to identify an enormous number of xenobiotics and respond appropriately? The answer contained here demonstrates that alternately spliced human CAR genes transcripts increase CAR’s capacity to serve as a selective xenosensor. Since rodent species appear incapable of producing some receptor splice variants, this finding is crucial to understanding the reasons behind the differences in response to chemical exposures observed for humans and rodents.
http://toxsci.oxfordjournals.org/content/120/2/381.full.html the link for the paper.