Cooperative regulation of expression of cytochrome P450 enzymes by aryl hydrocarbon receptor and vitamin D receptor

Abstract

Benzo[a]pyrene (BaP), a polycyclic aromatic hydrocarbon produced by cigarette combustion, is implicated as a causative agent of smoking-related diseases such as cancer and atherosclerosis. BaP activates the aryl hydrocarbon receptor (AHR) and induces the expression of genes involved in xenobiotic metabolism, including cytochrome P450 1A1 (CYP1A1). CYP1A1 is involved not only in BaP detoxification but also in its metabolic activation, which results in DNA adduct formation and reactive oxygen species production. The vitamin D receptor (VDR) mediates vitamin D signaling in the regulation of calcium metabolism, cellular growth and differentiation, inflammation, immunity, and cardiovascular function. VDR belongs to the NR1I subfamily of the nuclear receptor superfamily along with other nuclear receptors involved in xenobiotic metabolism. The active form of vitamin D3, 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), acts as a physiological VDR ligand and is catalyzed by CYP24A1, a VDR target gene. We have investigated cross-talk between the AHR and VDR signaling pathways. BaP effectively enhances 1,25(OH)2D3-dependent induction of CYP24A1 and inactivation of 1,25 (OH)2D3 by CYP24A1 in human monocyte/macrophage-derived cells. The effect of BaP on CYP24A1 induction is mediated by AHR activation and de novo protein synthesis. On the other hand, 1,25(OH)2D3 enhances BaP-induced transcription of CYP1A1 in these cells. VDR and AHR directly bind to specific elements in the human CYP1A1 promoter. Induction of CYP24A1 and CYP1A1 by the activation of VDR and AHR may contribute to BaP-mediated toxicity.