1,25-Dihydroxyvitamin D3 and 9-cis-Retinoids Are Synergistic Regulators of 24-Hydroxylase Activity in the Rat and 1,25-Dihydroxyvitamin D3 Alters Retinoic Acid Metabolism in Vivo

The RXR forms a heterodimer with the VDR to activate genes that are regulated by 1,25(OH)2D3. In the absence of RXRʹs ligand, 9-cis-RA, RXR appears to be a silent partner to VDR. The effect of 9-cis-RA on VDR/RXR heterodimer formation and 1,25(OH)2D3-mediated gene expression in vivo remains unclear. We examined the effect of exogenous 9-cis-RA or 9-cis-RA precursors, 9,13-di-cis-RA and 9-cis-RCHO, on 1,25(OH)2D3-mediated induction rat renal 24-hydroxylase. The rats were treated as follows: (1) vehicle; (2) 1,25(OH)2D3; (3) 1,25(OH)2D3 + 9-cis-RA; (4) 1,25(OH)2D3 + 9,13-di-cis-RA; (5) 1,25(OH)2D3 + 9-cis-RCHO; (6) 9-cis-RA; (7) 9,13-di-cis-RA; and (8) 9-cis-RCHO. 1,25(OH)2D3 was administered IP 18 h prior to sacrifice. The retinoids were administered every 4 h, starting 28 h prior to sacrifice. The last retinoid dose was administered 4 h prior to sacrifice. Treatment with 1,25(OH)2D3 alone increased 24-hydroxylase from 35 ± 6 (controls) to 258 ± 44 pmol/min/g tissue. When 1,25(OH)2D3 was administered with 9-cis-RA, 9,13-di-cis-RA, or 9-cis-RCHO, 24-hydroxylases were 568 ± 56, 524 ± 56, and 463 ± 62 pmol/min/g tissue, respectively. Furthermore, codosing of 1,25(OH)2D3 and 9-cis-retinoids resulted in higher circulating concentrations of 9-cis-RA and 9,13-di-cis-RA when compared to rats dosed with 9-cis-retinoids alone. This was shown to be due to 1,25(OH)2D3 increasing the half-life of 9,13-di-cis-RA by three to four times. These results show that 9-cis-RA can act synergistically with 1,25(OH)2D3 in the regulation of 24-hydroxylase in vivo. Additionally, 1,25(OH)2D3 regulates 9,13-di-cis-RA metabolism in vivo.