Journal
CURRENT DRUG METABOLISM
Volume 7, Issue 4, Pages 349-365Publisher
BENTHAM SCIENCE PUBL LTD
DOI: 10.2174/138920006776873526
Keywords
nuclear hormone receptor; xenobiotics; cholestasis; positive selection; metabolism. molecular evolution; bile salts; steroids
Funding
- NIGMS NIH HHS [K08 GM074238-01A1, K08 GM074238] Funding Source: Medline
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The NRII subfamily of nuclear hormone receptors includes the 1.25-(OH)-vitamin D3 receptor (VDR: NR111), pregnane X receptor (PXR: NR112), and constitutive androstane receptor (CAR: NR113). PXR and VDR are found in diverse vertebrates from fish to mammals while CAR is restricted to mammals. Current evidence suggests that the CAR gene arose from a duplication of an ancestral PXR gene, and that PXR and VDR arose from duplication of all ancestral gene, represented now by a single gene in the invertebrate Ciona intestinalis. Aside from the high-affinity effects of 1,25-(OH)(2)-vitamin D-3 on VDRs, the NR1I subfamily members are functionally united by the ability to bind potentially toxic endogenous compounds with low affinity and initiate changes in gene expression that lead to enhanced metabolism and elimination (e.g., induction of cytochrome P450 3A4 expression in humans). The detoxification role of VDR seems limited to sensing high concentrations of certain toxic bile salts. such as lithocholic acid. whereas PXR and CAR have the ability to recognize structurally diverse compounds. PXR and CAR show the highest degree of cross-species variation in the ligand-binding domain of the entire vertebrate nuclear hormone receptor superfamily, suggesting adaptation to species-specific ligands. This review examines the insights that phylogenetic and experimental studies provide into the function of VDR, PXR, and CAR, and how the functions of these receptors have expanded to evolutionary advantage in humans and other animals.
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