Vitamin D receptor activation enhances Benzo[a]pyrene metabolism via CYP1A1 expression in macrophages

Abstract

Benzo[a]pyrene (BaP) activates the aryl hydrocarbon (AHR) and induces the expression of xenobiotic metabolic genes, including cytochrome P450 (CYP) 1A1. CYP1A1 is involved not only in BaP detoxification but also in metabolic activation, which results in DNA adduct formation. Vitamin D receptor (VDR) also regulates expression of other xenobiotic metabolism genes, including CYP3A. We investigated the cross‐talk between AHR and VDR signaling pathways and found that 1α,25‐ dihydroxyvitamin D3 (1,25(OH)2D3) enhanced BaP‐induced transcription of CYP1A1 in human monocytic U937 cells and THP‐1 cells. 1,25(OH)2D3 alone did not induce CYP1A1 and 1,25(OH)2D3 plus BaP did not increase other CYP1 family (CYP1A2 or CYP1B1) mRNA expression in U937 cells. Combination of 1,25(OH)2D3 and BaP increased CYP1A1 protein levels, BaP hydroxylation activity and BaP‐DNA adduct formation in U937 cells and THP‐1 cells more effectively than BaP alone. The combined effect of 1,25(OH)2D3 and BaP on CYP1A1 mRNA expression in U937 cells and/or THP‐1 cells was inhibited by VDR knockdown and VDR or AHR antagonists. Electrophoretic mobility shift assays and chromatin immunoprecipitation assays showed that VDR directly bound to an everted repeat 8 motif in the human CYP1A1 promoter. Thus, induction of CYP1A1 by the activation of VDR and AHR may contribute to BaP‐mediated toxicity and the physiological function of this enzyme.