Reschly EJ , Bainy AC , Mattos JJ , Hagey LR , Bahary N , Mada SR , Ou J , Venkataramanan R , Krasowski MD .

K08-GM074238 NIGMS NIH HHS , K08 GM074238 NIGMS NIH HHS

	Figure 1. Chemical structures of 1α,25-(OH)2-vitamin D3 (calcitriol), 1α-hydroxyvitamin D2, testosterone, 5α-petromyzonol 24-sulfate (major sea lamprey bile salt), 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), and 6-formylindolo [3,2-b]carbazole. Select bond positions are numbered for the vitamins, testosterone, and 5α-petromyzonol 24-sulfate, and the lettering of the steroidal rings is indicated for calcitriol, 1α-hydroxyvitamin D2, and testosterone. The carbon atoms numbered for testosterone indicate the sites of hydroxylation in the species studied in this report.
	Figure 2. Concentration-response curves for activation of VDRs by vitamin D derivatives and 6-formylindolo [3,2-b]carbazole. The ordinate represents activation of VDR, relative to vehicle control, and normalized to the maximal activator (0.5 μM calcitriol for mouse and sea lamprey VDRs; 1 μM calcitriol for human, frog, and zebrafish VDRs; 20 μM 6-formylindolo [3,2-b]carbazole for Ciona intestinalis VDR/PXR). (A)-(E) Human (●), mouse (■), frog (○), zebrafish (□), and sea lamprey (◇) VDRs are all activated by vitamin D derivatives while the Ciona intestinalis VDR/PXR (Δ) is insensitive to all vitamin D compounds. (F) The planar molecule 6-formylindolo [3,2-b]carbazole activates most vertebrate VDRs (i.e., all except zebrafish VDR) weakly and the Ciona VDR/PXR at low micromolar concentrations.
	Figure 3. Enzyme induction in cultured primary zebrafish hepatocytes. (A) 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) and 3-methylcholanthrene (3-MC) both increase EROD activity in zebrafish hepatocytes, relative to vehicle-only control, following a 48-hour exposure. In contrast, 3,3'-diindoylmethane (DIM) causes a reduction in EROD activity relative to vehicle-only control. (B) 5α-androstan-3α-ol (androstanol), 5α-cyprinol 27-sulfate, phenobarbital, and TCDD cause a concentration-dependent increase in testosterone 6β-hydroxylation activity in primary zebrafish hepatocytes, relative to vehicle control, following a 48-hour exposure. (C) Androstanol, 5α-cyprinol 27-sulfate, phenobarbital, and TCDD all activate recombinant zebrafish PXR using a luciferase-based reporter assay system in HepG2 liver cells. All values are normalized relative to 20 μM androstanol (which is assigned an efficacy of 1) and to β-galactosidase expression. (D) Phenobarbital (PB; 2 and 3 mM), TCDD (1 nM), and androstanol (0.2 mM) all increase flurbiprofen 4-hydroxylation activity in primary zebrafish hepatocytes, relative to vehicle control, following a 48-hour exposure.
	Figure 4. Phylogeny of vitamin D receptors (VDRs, NR1I), pregnane X receptors (PXRs,NR1I2), and constitutive androstane receptors (CARs, NR1I3). See Methods for details on the phylogenetic analysis. Four key evolutionary transitions in ligand sensitivity (i.e., ability to be activated by ligands) are proposed and indicated by the labels A, B, C, and D underneath four branches. Label A indicates loss of ligand sensitivity in the Xenopus frog PXRs relative to other PXRs. The Xenopus laevis and Xenopus tropicalis PXRs have narrow ligand sensitivity (essentially to benzoate compounds only) compared to other vertebrate PXRs. Label B indicates broadening of ligand specificity relative to the ancestral receptor. This is supported by the broader ligand specificity of vertebrate PXRs relative to the Ciona intestinalis VDR/PXR. Label C indicates acquisition of sensitivity to certain bile acids, particularly lithocholic acid and its derivatives, in mammalian VDRs. All non-mammalian VDRs studied so far are insensitive to bile salts. Label D indicates acquisition of sensitivity to vitamin D, a property of all vertebrate VDRs but not the Ciona VDR/PXR.

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