PT  - JOURNAL ARTICLE
AU  - Joshua G. DeKeyser
AU  - Michael C. Stagliano
AU  - Scott S. Auerbach
AU  - K. Sandeep Prabhu
AU  - A. Daniel Jones
AU  - Curtis J. Omiecinski
TI  - Di(2-ethylhexyl) phthalate Is a Highly Potent Agonist for the Human Constitutive Androstane Receptor Splice Variant CAR2
AID  - 10.1124/mol.108.053702
DP  - 2009 May 01
TA  - Molecular Pharmacology
PG  - 1005--1013
VI  - 75
IP  - 5
4099  - http://molpharm.aspetjournals.org/content/75/5/1005.short
4100  - http://molpharm.aspetjournals.org/content/75/5/1005.full
SO  - Mol Pharmacol2009 May 01; 75
AB  - The human constitutive androstane receptor (CAR, CAR1) regulates the expression of genes involved in xenobiotic metabolism in the liver. The CAR gene uses multiple alternative splicing events during pre-mRNA processing, thereby enhancing the CAR transcriptome. Previous reports have identified two prominent human CAR variants, CAR2 and CAR3, that possess four- and five-amino acid insertions in their ligand binding domains, respectively. Unlike the constitutively active reference form of the receptor, we now demonstrate that CAR2 is a ligand-activated receptor and comprises approximately 30% of the reference transcript level in human liver tissues in human hepatocytes. Furthermore, we identify the common plasticizer, di(2-ethylhexyl) phthalate (DEHP), as a highly potent and uniquely selective agonist of CAR2. Results from reporter transactivation and mammalian two-hybrid assays reveal that DEHP activates CAR2 at low nanomolar concentrations, results further supported by analysis of CAR target gene expression in primary human hepatocytes. In addition, comparative genomic analyses show that the typical mouse, rat, and marmoset models of DEHP toxicity cannot accurately profile potential human toxicity because of these species' inability to generate a CAR2-like transcript. The discovery that CAR2 is an ultimate human DEHP receptor identifies a novel pathway modulating human DEHP toxicity with potential clinical implications for a subset of patients undergoing critical care medical interventions. U.S. Government work not protected by U.S. copyright